Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.

Introduction

HH signaling pathway was originally identified for its role in patterning the Drosophila embryo development. 1 When mutated, the larvae of Drosophila were covered with short barbed spines like a hedgehog. 2 As an evolutionarily conserved and highly organized signaling, HH signaling regulates numerous processes of vertebrates and invertebrates, such as embryogenesis, cellular development, epithelial-mesenchymal transition (EMT), and varieties of pathological variations. 3 , 4 HH signaling pathway plays a vital role in the regulation of homeostasis in various tissues, such as stem cells in musculoskeletal tissue and digestive system. 5 Moreover, Evidence-Based Medicine has shown that abnormal HH signaling is a considerable driver of tumorigenesis and malignancy. 6 Understanding the function of HH signaling offers potential therapeutic interventions. Some targeted tumor therapies have entered clinical trials as the mechanism of HH signaling pathway is further explored. 7 The current review aims to provide a comprehensive background on HH signaling pathway and highlight the recent advances of its role in homeostasis and tumorigenesis. It will also shed light on the available means and potential challenges of targeted therapies for HH signaling pathway-dependent cancer.

Hedgehog signaling

Introduction of Hedgehog signaling pathway

The initiation of Hedgehog signaling is based on the processing of Hedgehog ligands in secretory cells, where a dual lipid-modified amino-terminal (N-terminal) polypeptide of the autocatalytically cleaved precursor protein is formed. 8 Signal reception is achieved by conserved receptors on the cell membrane, including the 12-pass transmembrane protein Patched (Ptch) and the 7-pass transmembrane protein Smoothened (Smo). In the absence of hedgehog ligand, Ptch inhibits the activity of Smo causing pathway inhibition. When the hedgehog ligand binds to Ptch, the inhibition of Smo is lifted, thus continuing to activate downstream signaling. 9 In addition to this, the activation of hedgehog signaling requires co-receptors, which can be involved in the inactivation of Ptch.

In mammals, hedgehog signaling activation elicits a transcriptional response in the nucleus of the recipient cell that is mediated by glioma-associated oncogene (Gli) transcription factors. 10 Gli proteins include an amino-terminal transcriptional repression domain, a zinc finger DNA binding domain and a carboxy-terminal transcriptional activation domain. When transcription is not activated, Gli is processed by protein hydrolysis into the form of a repressor with a truncated carboxy-terminal activation domain, which inhibits the transcription of the target genes. 11 In addition, Suppressor of fused (Sufu), a negative regulator of Gli, is essential for pathway activity in mammals. 12

A particular aspect of mammalian hedgehog signaling is the transport of signaling molecules at all levels in the primary cilium. 13 The primary cilium consists of ciliary membrane, axoneme and basal body. The presence of intraflagellar transport (Ift) proteins on the axoneme mediates the transport of signaling proteins, and this transport mode can regulate the concentration of the corresponding proteins within the cilium. 14 In addition, primary cilia form compartments that are separated from the rest of the cytoplasm of the cell and thus provide a unique intracellular environment for pathway components. 15

Components of Hedgehog signaling pathway

In this part, we will briefly introduce the signaling process to understand the mechanism of HH signaling pathway in tissue homeostasis and tumorigenesis. A large body of researches have reported the core components of HH signaling pathway. This cascade includes extracellular Hedgehog ligands; cell surface receptors and co-receptors; Gli family transcription factors (Gli1-Gli3) containing zinc-lipid structures and numerous intracellular and extracellular co-regulators. 16

Extracellular Hedgehog ligands

Hedgehog ligands are paracrine signaling factors that can mediate communication between cells up to hundreds of micrometers away. 17 Three soluble extracellular Hedgehog ligands have been identified in vertebrates, including Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh), which have distinct distributions in different developmental stages and tissues. 18 , 19

Shh

Shh-triggered signaling is well documented for its critical role during embryonic and postnatal developmental processes. For example, Shh forms a ventral and dorsal concentration gradient in the neural tube, thereby directing neural progenitor cell fate in time and space as well as acting physiologically as a morphogenetic agent. 20 , 21 Moreover, Shh directs the growth of post commissural axons along the longitudinal axis of the spinal cord, acting as a major mediator during central nervous system development. 22 , 23 Collectively, Shh plays a vital role in the developmental regulation of various tissues such as skull, adrenal cortex, hair follicles and sweat glands. 24 – 27

Activation of Shh following synthesis on the endoplasmic reticulum of secretory cells involves lipidation by cholesterol molecules and palmitic acid moieties (Fig. 1 ). 8 The secretion of activated Shh serves a crucial role in regard to its biological function. Shh was first cleaved into a 19 kDa Shh amino-terminal polypeptide (Shh-N) and Shh carboxy-terminal polypeptide (Shh-C). Then, Shh binds cholesterol to the carboxyl terminus of Shh-N through a protein hydrolytic cleavage process, whereas, Shh-C exits the endoplasmic reticulum and enters the proteasome to be degraded, ending its mission. 28 , 29 In general, palmitoylation occurs after cholesterol modification, further increasing Shh activity. 30 Palmitoylation of Shh is mediated by HH acyltransferase (Hhat), which transfers palmitic acid to the amino-terminal cysteine residue of Shh-N. 31 , 32 The activated form of Shh is a dual lipidation of cholesterol and palmitic acid by Shh-N (Fig. 2a ). 20 Fig. 1 Activation and spread of hedgehog ligands in secretory cells. The three vertebrate hedgehog ligands Shh, Dhh and Ihh have similar secretion processes, differing slightly in the tissue distribution of the three. The figure shows the secretion of Shh as an example of the secretion process of hedgehog ligands. Activation of Shh occurs in the endoplasmic reticulum (ER). The Shh precursor is first processed into two parts, Shh-N and Shh-C. The carboxyl terminus of Shh-N is bound to cholesterol by a protein hydrolytic cleavage process, while the amino terminus of Shh-N is bound to palmitic acid mediated by Hhat. In contrast, Shh-C is degraded after being transported out of the ER. There are several mechanisms for the diffusion of Shh-N out of secretory cells after activation: a Shh-N is mainly transported out of secretory cells by the synergistic action of Disp1 and Scube2. b The polymerization of monomer-activated Shh-N into multimolecules facilitates the diffusion of ligands. c Hspg is localized to the secretory cell membrane, which recruits lipoprotein. Shh-N is loaded on the lipoprotein as a "passenger" for long-distance transportation. d Ptch1 on the surface of the receiving cells has a negative feedback regulation on the release of Shh-N Fig. 2 Three-dimensional structure of Shh, Ptch1 and Smo. a The structure of the activated Shh. b The structure of Ptch1. c The structure of Smo. d The structure of the 1Shh:2 Ptch1 complex. Ptch1-A binds to Shh at the interface of its calcium and zinc binding sites, which drives Ptch1 degradation. Ptch1-B binds to the N-terminal palmitoyl and C-terminal cholesterol modifications of Shh and anchors to the core of Ptch1 protein, which decreases the protein activity of Ptch1. e Mechanism of Smo inhibition by Ptch1. Ptch1 regulates the binding of sterols to Smo, and hence inhibits the activity of Smo. Three possible mechanisms are shown by the black arrows. a Sterols move from the outer leaflet of the membrane to ECD1 via Ptch1, which depletes the sterols inside the membrane. b Ptchl inhibits Smo activity by decreasing its accessibility to sterols from the inner leaflet of the membrane. c Ptch1 accepts sterols from CRD and transports them to the membrane, thereby inhibiting Smo activity

The mechanism by which the diffusion of activated Shh from secretory cells occurs is more complex (Fig. 1 ). Dispatched-1 (Disp1), a 12-transmembrane protein, is required for the secretion of activated Shh. Recent studies suggest that Disp1 binds cholesterol molecules of Shh-N and, together with Scube2, a secreted glycoprotein, transports Shh out of the cell. 33 , 34 If the cholesterol and palmitic acid of Shh are broken down, Shh is also degraded. 35 In addition, monomer-activated Shh-N can polymerize into multimolecules, a form that naturally facilitates the long-distance transport of ligands. 36 Heparan sulfate proteoglycan (Hspg) is localized on the surface of secretory cell lipid membranes, where it interacts with Shh-N and recruits the lipoprotein lipophorin, resulting in the loading of Shh-N on lipoprotein for transport. 37 – 39 In addition to the ability of secretory cells to positively regulate Shh secretion, Ptch1, which receives Shh receptors on the cell surface, is able to participate in the negative feedback regulation of ligands, limiting the range of Shh signal waves. 40 In conclusion, Shh is able to assemble into suitable carriers for transport, and other possible mechanisms that help Shh diffusion deserve further investigation.

Dhh and Ihh

Dhh and Ihh act more specifically than Shh and show pronounced tissue specificity. Dhh is a key regulator of gonadal tissue development, especially in ovarian granulosa cells and spermatogenesis. 41 , 42 Expressed by Sertoli cells, Dhh directly mediates the proliferation and differentiation of spermatogonia through the regulation of downstream signaling pathways. Dhh-deficient animals exhibit abnormal testicular mesenchymal cell differentiation and defective peritubular cell morphology, resulting in sterility in male mice. 43 The function of Ihh is mostly related to chondrocyte differentiation in the skeleton. 44 It regulates the differentiation of growth plate chondrocytes through a negative feedback mechanism of parathyroid hormone-related proteins, and also directly controls chondrocyte proliferation and osteoblast function. 45

The activation and secretion of Dhh and Ihh are similar to that of Shh. Dhh and Ihh also undergo autocatalytic cleavage to form Dhh-N and Ihh-N, in which the C-terminal structural domain is removed. 46 This N-terminal structural domain is then modified by N-terminal palmitoylation as well as the cholesterol addition of C-terminal amino acids, resulting in the formation of the mature proteins Dhh-N and Ihh-N. 47 All three HH ligands share high sequence homology, similar overall fold and are capable of binding to and activating the same signaling pathway receptors. They mainly differ in their N-terminal amino acid sequence; however, their N-terminal sequence similarity may also reach 76–91%. 48

Over the years, it has also become increasingly clear that Dhh and Ihh have multiple functions in other tissues. For instance, full-length Dhh plays a critical role in regulating vascular endothelial integrity. 49 The potential roles of Dhh and Ihh in varies organs requires further investigation.

Receptors and co-receptors

Ptch

Ptch, the 12th transmembrane HH receptor, has two homologs, Ptch1 and Ptch2. 50 The structure of Ptch1 includes the transmembrane structural domain (TMD), which comprises a sterol-sensing structural domain (SSD) and two extracellular structural domains (ECD1 and ECD2) (Fig. 2b ). 51 Various researchers have suggested that Ptch1 acts as a major receptor for HH ligands. Here, modifications of Shh-N may occur in its interaction with Ptch1. 52 In addition, molecular evidence has shown that Ptch1 is able to recognize the calcium-mediated interface of Shh-N. Moreover, the binding mode of Shh and Ptch1 has been reported to be the formation of the 1 Shh:2 Ptch1 complex (Fig. 2d ). 53 However, in vivo studies have revealed that co-receptors can form a heterotrimeric complex with Ptch1 and HH-N and induce cell proliferation or embryonic development. 29 Nonetheless, how HH recognizes and inhibits Ptch1 continues to remain controversial.

While the role of Ptch2 is inadequately understood, it compensates the response to Shh in the absence of Ptch1. 54 Ptch2 may be able to bind HH proteins in different cellular environments in order to regulate the subsequent signaling pathway. 55

Smo

In-depth structural and functional studies have revealed the role of the two variable ligand binding sites, seven-pass α-helical transmembrane bundle (TMD) and extracellular cysteine-rich domain (CRD) of Smo, a G protein-coupled receptor, in regulating Smo activity (Fig. 2c ). 56 , 57 The TMD and extracellular loops form a ligand-binding region. 58 CRD at the extracellular amino terminus mediates Smo dimerization. In addition, intracellularly, the carboxy-terminal tail mediates the conformational change of the Smo dimer. In the absence of ligand, the carboxyl terminus is in a closed conformation, obscuring the kinase binding site; in the presence of ligand, the carboxyl terminus ser/thr cluster is highly phosphorylated, forming an open conformation. 59 – 61

In the absence of ligand stimulation, Ptch inhibits Smo to block the cascade reaction. The question of how Ptch inhibits Smo remains relatively mysterious. Most scholars believe that Ptch can modulate the binding of lipid Smo ligands to Smo, which can inhibit Smo activity. These endogenous inhibitory molecules usually refer to sterols or their derivatives (Fig. 2e ). 20 , 62 , 63 The inactive Smo is located in the cytoplasm. However, when HH binds to Ptch, the restrictive effect of Ptch on Smo is lifted to initiate downstream signaling pathways. 64 , 65 Ptch is transported to lysosomes in the cytoplasm for degradation. Smo activation requires two mechanisms: first, Smo needs to be translocated to primary cilia, a microtubule-based organelle (Fig. 3 ); second, Smo localized to cilia undergoes carboxy-terminal phosphorylation. 66 , 67 A recent study found that cholesterol covalently bound to the D95 residue of the CRD of Smo is required for Smo activation, a process that results from calcium-promoted autocholesterolization of Smo. 68 , 69 Fig. 3 Primary cilia play a key role in HH signaling pathway. Primary cilia are composed of ciliary membrane, axoneme and basal body. The proper functioning of HH signaling relies on the Ift mechanism. Ift-B complex protein and Ift-A complex protein together constitute Ift trains that carry motors with HH signaling components sliding on the axoneme. Kinesin mediates transport from the base to the tip of the cilium, while dynein2 mediates transport from the tip to the base of the cilium. a Receptor cells are closed to signal transduction. In the absence of hedgehog ligand, Ptch1 inhibits Smo. Lipid Smo inhibitors bind to the TMD region of Smo, inhibit Smo activity, and constrain Smo to the cytoplasm. Gpr161 localizes to the cilia in the presence of Ift-A and Tulp3. Gpr161 induces PKA activity, and PKA phosphorylates the Sufu/Gli complex. Kinesin Kif7 then transports the complex to the cilia tip. Sufu is further phosphorylated by GSK3β; Gli is further phosphorylated by CK1 and GSK3β. The complex then dissociates and Gli is processed by protein hydrolytic cleavage to Glir, which subsequently enters the nucleus to repress target gene transcription. b Receptor cells are open to signal transduction. In the presence of Hedgehog ligand, the inhibition of Smo by Ptch is released and Ptch is transported to the lysosome for degradation. The co-receptors Boc and Gas1 can interact with Ptch1 and Ptch2 to form a receptor complex respectively, thereby promoting or inhibiting signal transduction. The concentration of intracellular lipid Smo inhibitor ligands decreases and Smo forms an activated dimeric form that is transported by Kinesin Kif3 and Evc-Evc2 proteins to the cilia membrane near the basolateral. The Smo carboxyl terminus is then fully activated by phosphorylation of CK1 and GRK2. After Smo activation, Gpr161 returns to the cytoplasm. Meanwhile, activated Smo inhibits PKA activity and is not sufficient to phosphorylate the Sufu/Gli complex. The unphosphorylated complex is transported to the cilia tip by Kinesin Kif7. The unphosphorylated Sufu is degraded by ubiquitination; Gli is phosphorylated by CK1 to form Glia. Glia enters the nucleus to promote the transcription of related target genes, such as Ptch1/2, which acts as a negative regulator of signal transduction, Gli1, which amplifies signals, Bmi1, which encodes a transcriptional repressor, and Myc, Cyclin D, and Cyclin E, which encode cell cycle regulators

Co-receptors

Brother of Cam-related/downregulated by oncogenes (Boc) and growth arrest-specific 1 (Gas1) have been identified as co-receptors regulating HH signaling pathway activity. The specific heterogeneous complexes formed by their interaction with Ptch1/2 receptors, respectively, can mediate different kinetic Smo depression programs through distinct ligand reception patterns. 70 , 71 Notably, Boc sometimes acts as an inhibitor of HH signaling pathway during craniofacial tissues development. 71 In addition, Hspg can act as co-receptors for neuronal cell development through glypican 5 core protein and 2-O-sulfo-iduronic acid structures. 72

Gli family transcription factors

Upon excitation of HH signaling pathway, Gli transcription factors are activated thereby regulating target gene expression. The vertebrate homologs of this Drosophila Cubitus interruptus transcription factors include Gli1, Gli2, and Gli3 proteins. Gli1 is exclusively a transcriptional activator, whereas Gli2 and Gli3 have dual activity. Although both contain highly similar zinc finger structural domains that can bind to DNA, Gli3 often acts as a transcriptional repressor because the process of protein hydrolysis is most pronounced at Gli3, while Gli2 acts primarily as a transcriptional activator. 73 , 74 Through protein hydrolysis, they act as bifunctional transcription factors, changing from the full-length transcriptional activator form (Glia) to the carboxy-terminal truncated transcriptional repressor form (Glir). 11 GLI-similar (Glis) transcription factors, a subfamily highly similar to Glis, can also undergo nuclear translocation by post-translational modifications in the cytoplasm, and their potential interconnection with Gli1-3 enriches the Gli network. 75 – 77

Gli protein activity can be regulated by protein-protein interactions. Sufu, a negative regulator of Gli1-3, was shown to abduct Gli1-3 in the cytoplasm to prevent it from undergoing nuclear translocation. 12 , 78 , 79 In cells, Sufu is phosphorylated by Protein kinase A (PKA) to form a stable phosphorylated form of Sufu, which affects its interaction with Gli. 80 Sufu and Gli form a complex in the cytoplasm after entering the primary cilia (Fig. 3 ), resulting in different phosphorylation states of the two proteins and determining Glia or Glir production, depending on the presence or absence of hedgehog ligand stimulation. 81 In the absence of ligand stimulation, the Sufu/Gli complex is in a closed conformation; after ligand stimulation, Sufu assumes an open conformation in the complex. The different phosphorylation states of both proteins cause conformational changes that lead to dissociation of the Sufu/Gli complex and entry of Gli into the nucleus to regulate target gene expression. 82 , 83

Hedgehog signaling pathway target genes

HH signaling pathway plays an essential role in cell proliferation and differentiation, tissue development, homeostasis and EMT. 3 , 16 Its complex regulatory network influences the transcription of divergent target genes that vary between tissues and cell types (Table 1 ). In most cells responsive to HH signaling, the common target genes include Ptch1/2 and Gli1. 84 Moreover, increased expression of the Ptch1/2 and Gli1 genes have been shown indicate an activated HH signaling pathway and could provide negative (Ptch1) and positive (Gli1) regulation of HH signaling with feedback loop mechanisms. Furthermore, in tissue-specific stem cells, HH signaling induces Bmi1, which acts as a transcriptional repressor that regulates the proliferative capacity of cells. 85 Numerous target genes in this pathway are cell cycle regulators, such as Myc, CyclinD, and CyclinE, as well as development-related regulators, such as Fgf4 and Hhip. 86 – 89 In the developing neural tube, this pathway regulates the Nkx6.1, Olig2, Nkx2.2, and FoxA2 genes, conferring ventral neural fates and has Gli-binding sites in the regulatory regions. 90 In addition, HH signaling pathway promotes the expression of certain genes, including Snzi1, Zeb1, Twist2 and Foxc2, which enhance epithelial mesenchymal transition. 91 Other target genes include the apoptosis regulator Bcl2, Vegfa, Abcg2, Mycn, Foxm1, Pax6, Pax7, Pax9 and Jag1, as well as members of the Wnt signaling pathway. 92 – 98 In summary, HH signaling pathway can regulate the corresponding target gene transcription in different functional states and cell types. Table 1 Hedgehog signaling pathway target genes Target gene Full name of the gene Function of the gene products Ptch1 84 Patched 1 Receptor that initiates signaling pathways, negative feedback regulation Ptch2 84 Patched 2 Receptor that initiates signaling pathways Gli1 84 Glioma-associated oncogene 1 Direct transcriptional activator, positive feedback regulation Bmi1 85 Bmi1 proto-oncogene Transcriptional repressor regulating the proliferative capacity of cells Myc 86 Myc proto-oncogene Cell cycle progression, apoptosis and cellular transformation CycD and CycE 87 CyclinD and CyclinE Cell cycle progression Fgf4 89 Fibroblast growth factor 4 Involved in varieties of biological processes including embryonic development, cell growth, morphogenesis, tissue repair and invasion Hhip 88 Hedgehog interacting protein Involved in varieties of developmental processes including anteroposterior patterns of limbs and regulation of left-right asymmetry in embryonic development Nkx6.1 90 NK6 homeobox 1 Required for the development of beta cells Nkx2.2 90 NK2 homeobox 2 Involved in the morphogenesis of the central nervous system Olig2 90 Oligodendrocyte transcription factor 2 Regulator of ventral neuroectodermal progenitor cell fate FoxA2 90 Forkhead box A2 Transcriptional activators that regulate the specificity and differentiation of dopaminergic neurons Snai1 91 Snail family transcriptional repressor 1 Critical for mesoderm formation in the developing embryo Zeb1 91 Zinc finger E-box binding homeobox 1 Associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy Twist2 91 Twist family bHLH transcription factor 2 Inhibitors of osteoblast maturation, maintaining the pre-osteoblast phenotype of cells during osteoblast development Foxc2 91 Forkhead box C2 Involved in the development of mesenchymal tissues Pax6, Pax7 and Pax9 97 Paired box 6, 7 and 9 Involved in the development of neural tissues

Hedgehog signaling and the primary cilium

Unlike other signaling pathways, the normal maintenance of the vertebrate canonical HH signaling pathway is highly dependent on primary cilia. Primary cilia recruit extracellular signaling components that link the extracellular environment, where signals are complex and diverse, to the intracellular environment. 13 , 99 This section will briefly describe the structural features of primary cilia and the way in which the key components of HH signaling pathway act in primary cilia.

Brief introduction of primary cilia

The primary cilium is a specialized structure located on the cell surface. 100 The axoneme of primary cilia includes 9 microtubule doublets in the outer ring, while lacking the central 2 microtubule singlets (known as 9 + 0 axoneme). Primary cilia are anchored to the cell by basal body, which is specialized from the mother centriole and contains a number of proteins for ciliogenesis and assembly. 101 , 102 Between the cilia and basal body is the ciliary transition zone, which regulates protein transport within the cytoplasm and cilia. 103

The transport of protein molecules within primary cilia to the cytoplasm is achieved through the Ift mechanism. 14 Ift is driven by two molecular motors, involving cytoplasmic dynein2, which mediates transport from tip to base, and the heterotrimeric kinesin-2 complex comprised of Kif3a, Kif3b, and Kap3, which is responsible for transport from base to tip. 15 , 104 , 105 Mutations in the gene encoding the heavy chain of cytoplasmic dynein2 cause axoneme swelling because Ift-related proteins are trapped in cilia due to disruption of retrograde transport. 14 Gli cooperates with Kif3a and Kap3, where the interaction of Kap3 restricts Gli transcriptional activity. 106 Ift-B complex protein and Ift-A complex protein together constitute Ift trains that bridge kinesin motors with HH signaling molecules. 107 Ift trains slide back and forth along the axoneme and are responsible for cilia structure assembly and balancing. Periodic binding of Ift-A, Ift-B and dynein2 can balance the protein entry and exit of cilia, effectively preventing the accumulation of material. 108 , 109 Huang et al. showed that wimple mutants disrupting Ift172, an Ift-B protein, lacked the normal primary cilia structure, which resulted in the inability of the receiving cells to respond to Shh. 110

Changes in the structure and function of primary ciliary protein fractions can have an impact on HH signaling pathway. Defective RNAi of Kinesin Kif14 disrupts the function of distal appendage proteins Sclt1 and Fbf1, which results in a defective basal body that fails to activate HH signaling pathway. 111 Disruption of most primary ciliary proteins decreases signaling activity, but some proteins are altered in different ways that enhance pathway activity; thus, changes in ciliary structure have a bidirectional effect on the HH signaling cascade response, with subsequent effects on cell fate. 15 , 112

Hedgehog signaling functions through primary cilia

Smo and primary cilia

The ciliary membrane contains a specific receptor for HH signaling pathway, Ptch, which is essential for receiving the initial signal from the outside. 113 , 114 In the absence of Hedgehog ligand, Ptch induces a closed conformation of Smo by controlling the TMD binding of small lipid Smo ligands to Smo, allowing Smo to remain in the cytoplasm (Fig. 3a ). 63 , 115 In the presence of Hedgehog ligand, Ptch derepresses Smo and Smo activates. Activation of Smo involves its localization to the ciliary membrane and carboxy-terminal phosphorylation. 59 , 116 – 118 First, the concentration of small lipid Smo inhibitors in the cytoplasm decreases and Smo transforms into an open conformation and is transported to the ciliary membrane by the action of the kinesin Kif3. 119 , 120 Besides, after reaching the cilia, the activation of Smo depends on the concentration of Hedgehog ligands. When there is no sufficient ligand to stimulate the signal, the small lipid Smo inhibitor rapidly binds to the TMD again and the Smo changes back to a closed conformation and returns to the cytoplasm. 121 When stimulated by sufficient Hedgehog ligands, the Smo carboxyl terminus is fully activated by casein kinase 1 (CK1) and G protein-coupled receptor kinase 2 (GRK2) phosphorylation (Fig. 3b ). 60 , 61 It can be seen that Smo acts in a Gαi - coupled Gpcr manner, which is highly sensitive to changes in Hedgehog ligand concentration.

Gli and primary cilia

In the absence of Hedgehog ligands, Gpr161, a G protein-coupled receptor, enters the cilia and localizes to the ciliary membrane via Ift-A and Tulp3, a member protein of the vertebrate tubby-like family. 122 , 123 Then, in the presence of adenylate cyclase 5/6 (Ac5/Ac6), cAMP increases and activates PKA, which phosphorylates both proteins of the Sufu/Gli complex. 124 , 125 Gli is further phosphorylated by CK1 and Glycogen Synthase Kinase-3 (GSK3β) and forms Glir by proteolytic cleavage (Fig. 3a ). 123 , 126 , 127

In the presence of Hedgehog ligands, Kinesin Kif7 dephosphorylates and then aggregates at the tip of primary cilia, in parallel with the return of Gpr161 to the cytoplasm. 128 , 129 Gαi inhibits Ac5/Ac6 and reduces PKA activity after intraciliogenic activation. 130 – 132 In addition, Evc-Evc2 proteins, which localize active Smo at the base of the cilia, also inhibit PKA activity. 133 The Sufu/Gli complex, which is not phosphorylated by PKA, is transported to the cilia tip by Kinesin Kif7 and accumulates there. 134 Within the cilia, unphosphorylated Sufu is degraded by Scf-mediated ubiquitination; however, Gli is phosphorylated by CK1 to form Glia. 135 Then the complex dissociates and Glia enters the nucleus to mediate the transcription of target genes (Fig. 3b ). 117 , 121

Because CK1 and GSK3β, which are required for the phosphorylation process of the Sufu/Gli complex, are present in primary cilia, primary cilia are necessary to determine the form of Gli. 136 Furthermore, the cilium is a local compartment relative to the cytoplasm, therefore small changes in PKA activity can be detected in the little space, which determines changes in Glia versus Glir. 125 , 137

Hedgehog signaling in homeostasis

Well known for its crucial role in regulating the embryonic and postnatal development of vertebrate, HH signaling pathway has been proven to orchestrate the specific formation and morphogenesis of an organism. 5 , 99 , 138 , 139 Meanwhile, HH signaling pathway has been demonstrated to express continually in many adult mammalian tissues and organs, especially in the epithelial and mesenchymal cells, maintaining the homeostasis of adult tissues and organs via regulating a great variety of quiescent stem cell populations as well as the epithelial-mesenchymal interactions. 99 , 140 , 141 This part of review outlines recent discoveries on the crucial roles of HH signaling pathway in the homeostasis of multiple tissues and organs possessing representative characteristics.

HH signaling pathway maintains the homeostasis in the mesenchyme

HH signaling pathway is one of the major signaling pathways regulating osteogenesis and post-embryonic long bone homeostasis with postnatal expression in the mesenchyme. 142 , 143 Yang et al. found that silencing Ift80 impairs cilia formation and reduces HH signaling pathway expression in bone. 144 Ift80 increases the expression of osteoblast markers by regulating HH/Gli pathway, demonstrating that HH signaling pathway plays a remarkable role in maintaining osteoblast differentiation and mineralization. Ihh upregulates mesenchymal stem cells (MSCs) and osteoblast markers. Tissue engineering experiments utilizing Ihh-MSCs-scaffold complex has shown increased bone repair capacity. 145 Shh is a potential signaling molecule that regulates osteoblast differentiation. Armstrong et al. have shown that Shh in zebrafish can upregulate the expression of Sp7 in osteoblast lineage cells and increase the proliferation of osteoblasts. 146

The calvarial bone has become an emerging model for studying the function of HH signaling pathway in bone homeostasis. Regarded as the primary niches for osteogenesis, craniofacial sutures contain MSCs. 140 , 147 , 148 Zhao et al. revealed that cells harboring MSCs characteristics were Gli1 + . These MSCs play a significant role in regulating calvarial bone formation and injury repair. 147 Using diphtheria toxin to disentangle Gli1 + cells led to premature fusion within the cranial sutures, resulting in craniosynostosis, indicating the vital role of HH signaling pathway in controlling the suture homeostasis and calvarial bone patterning and repair. 147 , 149 Moreover, the interplay between BMP and Ihh signaling has been identified in maintaining suture homeostasis via interaction among MSCs, osteoprogenitors, and osteoclasts during calvarial bone formation and repair. 150

Skeletal muscle has the ability to repair damage due to the presence of muscle stem cells, namely, myosatellite cells. 151 Myosatellite cells normally maintain a quiescent condition and give rise to myogenic cells and reform the myofibers of the muscle in response to injury. 152 Study showed that muscle injury could stimulate Shh expression. When Shh signaling was inhibited, the expression of Myf5 and MyoD was impaired, accompanied by reduced number of activated myosatocytes. 153 Similarly, Koleva et al. showed that Shh could promote the proliferation of myosatellite cells and myotube fusion. 154 Subsequently, Elia et al. found that Shh can promote the differentiation of chicken primary myoblasts, and this effect can be inhibited by cyclopamine, an inhibitor of Shh signaling. 155 It has also been reported that Shh promotes the expression of Pax7, Myf5, MyoD, MyoG, and MyHC in mouse myoblasts, and the promotion of these genes by Igf-1 depends on HH signaling pathway. 156 , 157 Further study by Voronova et al. showed that Gli2 formed a protein complex with MyoD and Mef2c to enhance the transcription factor activity of MyoD. 158 MyoD regulates the activity of HH signaling pathway, which allows Gli2, Mef2c, and MyoD to form a reciprocally regulated recycling network. Devakanmalai et al. reported that HH signal affects muscle cell differentiation by activating MyoD and Myf5, and then regulating Mef2c. These studies indicate that HH signaling pathway is essential for postnatal muscle homeostasis. 159

HH signaling pathway may also participate in smooth muscle regeneration and differentiation. Kramann et al. found that adventitial MSC‐like Gli1 + cells were progenitors of vascular smooth muscle cell and expressed CD34, Sca1, and Pdgfrβ, possessing tri-lineage differentiation capacity towards osteoblasts, adipocytes, and chondrocytes. 160

HH signaling pathway maintains the homeostasis in epithelial tissue

During the hair cycle, Shh signaling pathway is essential for maintaining hair follicle stem cell populations and regulating the development of hair follicles and sebaceous glands, meanwhile regulating epithelial-mesenchymal interactions. 161 , 162 Mammalian epidermal metabolism is maintained by the continuous proliferation of epidermal stem cells. 163 Adolphe C et al. found that Ihh overexpression did not result in any significant epidermal morphogenetic phenotype, while overexpression of Dhh was indistinguishable from Shh. The phenotypes were resulted from dysregulation of stem cell activity, including hyperplasia of epidermal progenitors and almost complete loss of epidermal tissue renewal capacity, indicating that HH activity is the vital factor to maintain homeostasis of epidermal stem cells. 164 Zhou et al. showed that Shh, its receptors Ptch1, Smo and its downstream transcription factor Gli1 were detected in the basal layer of fetal epidermis and in newly sorted human putative epidermal stem cells (HPESCs). 165 HPESCs treated with medium containing Shh-N exhibited enhanced cell proliferation. In contrast, cyclopamine inhibits Shh and thus prevents proliferation. Similarly, the mitogenic effect of epidermal growth factor on HPESCs can be eliminated by cyclopamine. In addition, the expression of Bmp-4, a potential downstream effector of Shh signaling, can increase HPESCs proliferation. 165 Shh signaling in mammalian skin controls hair follicle epithelial cell growth and morphogenesis by regulating Gli transcription factors. 166 Shh expression and the ability of skin cells to respond to Shh signaling pathways are spatially and temporally regulated during the hair cycle. 167 Knockout of Shh-dependent Sox9 in the skin results in the appearance of external hair, with severe proliferation defects and difficulty in forming a stem cell microenvironment. 168 Additional studies have shown that the demand for substrate formation by β-catenin occurs downstream of Tabby/Downless and upstream of Bmp and Shh. 169

Intestinal epithelial homeostasis is regulated by a strictly controlled balance between intestinal stem cell (ISC) proliferation and differentiation. 170 Villin-Cre;Ihh flox/flox mutant mice show a significantly reduced number of villi and reduced cell proliferation in the stem cell compartment, suggesting that Ihh is essential for ISC regeneration and differentiation. 171 Specifically, deletion of Ihh in intestinal epithelial is accompanied by an increase in epithelial Wnt signaling pathway, while the activation of the Wnt pathway is a common cause of intestinal tumorigenesis. 172 , 173 HH might have a tolerogenic influence as a regulator of inflammation. 174 Lees et al. showed the reduced expression of HH signaling pathway in individuals with inflammatory bowel disease and ulcerative colitis. 175 Dop et al. conditionally deleted Ihh in adult mice and found an inflammatory response accompanied crypt changes, resulting in influx of macrophages and fibroblasts into the villus core. 176 Recent studies suggest that more than one target cell population (e.g., macrophages, dendritic cells) is relevant to HH-modulated inflammation. 177 , 178

HH signaling pathway maintains the homeostasis via regulating epithelial-mesenchymal interaction

Epithelial-mesenchymal interactions coordinated by HH actively maintain homeostasis and regulates repair and regeneration in lung. 179 Tien et al. found proliferative expansion of the adjacent lung mesenchyme when specifically deleting Shh in the murine lung. 180 Reduced expression of HH signaling pathway is initially detected during the acute phase of epithelial injury as the mesenchyme proliferates in response, whereas being upregulated to the baseline while the homeostasis is restored. However, Liu et al. demonstrated the upregulated HH signaling pathway in lung fibrosis or airway injury, supported by a proliferation in stromal Gli1 + cells in adult mice. 181 Moreover, when confronted with an airway injury, Shh overexpression enhances collagen deposition and lung fibrosis.

Both epithelial and mesenchymal compartments of the rodent incisors continue to grow and regenerate throughout the lifespan of animals and requires constant repair. It has been identified that during the growth of the mouse incisor, Shh plays a significant role in maintaining the ability of stem cells to expand the ameloblast lineage in the incisor epithelium, indicating that Shh regulates the homeostasis of mouse incisor enamel, the epithelial compartment of incisors. 182 Meanwhile, Shh signaling pathway also plays an important role in the homeostasis and regeneration of dentin, the mesenchymal compartment of incisors. Zhao et al. identified that Gli1 + MSCs were localized around arteries and the accompanying nerves, while the HH ligand that maintains the Gli1 + MSC population was secreted by nerves in the neighboring neurovascular bundle (NVB). 183 In addition, Gli1 + cells were also indicated to contribute to incisor injury repair by generating reparative dentin.

Unlike the rodent incisor, the rodent molar does not possess the property of continuous growth, and the majority of Gli1 + cells were distributed within the mesenchyme, mainly in the periodontal ligament near the molar apical. These cells were activated and significantly contributed to the bone remodeling when imposed on the orthodontic forces. 184

Hedgehog signaling in cancer

Cancer is one of the major causes of death in the world. Almost ten million cancer deaths were expected in 2020. 185 Cancers are highly burdensome diseases, which have negative physical and mental effects on patients, as well as serious economic consequences. HH signaling pathway has been documented to be responsible for tumor initiation and premalignant lesion as well as tumor progression leading to a greater tumor size and more invasive behavior. 186 – 188 Tumor metastasis and the resistance to anti-cancer therapy (radio and chemo-resistance) were the ultimate challenges to fight cancer as a life-threatening disease. 189 , 190 Also, cancer stem cell (CSC) with the self-renewal ability not only has a close relationship with multiple tumor properties mentioned above such as tumor initiation, development, metastasis, and tumor recurrence. 191 Therefore, we mainly discussed the decisive role of HH signaling pathway in five aspects including cancer initiation, cancer progression, metastasis, resistance to anti-cancer therapy, and cancer stemness in different organs in this section (Fig. 4 ). Fig. 4 Summary of types of cancer caused by dysregulation of HH signaling pathway. The inner circle present five aspects of tumor biological behavior which are influenced by HH signaling pathway. The outer circle shows the representative cancers discussed in the review. The online resources in the picture were obtained from the website: www.699pic.com and www.vecteezy.com

Cancer cells in conjunction with the surrounding oncogenic stromal components form the tumor. Microvascular components, fibroblasts, endothelial cells and other noncellular elements in the tumor stroma determine the multiple behaviors of tumors, such as tumor initiation, progression, and resistance to anticancer therapy. 192 The interplay of HH signaling pathway between cancer cells and the stroma component may be overall described using the following models. Mutations of HH signaling pathway components, such as Ptch and Smo, drive ligand-independent HH signaling pathway activation, which can lead to systemic disease and manifest with a variety of symptoms, such as Gorlin syndrome. Cancer cells have also been shown to secrete HH ligands in an autocrine manner in cancer progression. 193 , 194 In addition, ligand-dependent activation of the HH pathway in tumors have been shown to adopt a paracrine or a reverse-paracrine manner. 195 , 196

A plethora of studies have supported the presence of a dynamic interaction via mutual transmission of HH signaling molecules between tumor cells and stromal cells. Coexistence of such HH ligand interactions in different types of tumors has also been shown to be conclusive. The association of HH signaling pathways with different cancers, including changes in related molecules, secretory mechanisms, and tumor characteristics were summarized (Table 2 ). Table 2 Changes of HH signaling pathway in cancer Cancer Mechanism HH signaling pathway-related molecules Biological behavior influenced by HH signaling pathway Craniofacial Complex Oral squamous cell carcinoma 198 , 199 ligand-dependent Ptch1 (+), Shh (+), Smo (+), Gli1 (+) Initiation (+), Progression (+), Metastasis (+) Odontogenic karatocytes 211 ligand-independent Ptch1 (+), Smo (+) Progression (+) Brain Medulloblastoma 226 , 230 , 232 ligand-independent Ptch1 (+), Shh (-) Stemness (+), Progression (+), Resistance (+) Glioma 237 , 510 ligand-dependent Shh (+), Gli2 (-) Progression (+), Metastasis (+) Renal Renal cell carcinoma 249 , 254 , 255 , 511 ligand-dependent Shh (+), Smo (+), Gli1 (+), Gli2 (+) Stemness (+), Progression (+), Resistance (+) Prostate Prostate cancer 259 , 263 , 512 ligand-dependent Shh (+), Smo (+) Stemness (+), Progression (+), Resistance (+) Liver Hepatocellular carcinoma 266 , 267 , 271 , 274 ligand-dependent Ptch1 (+), Smo (+), Gli1 (+) Progression (+), Metastasis (+), Resistance (+) Cholangiocarcinoma 276 , 282 , 513 ligand-dependent Gli1 (+), Gli2 (+) Stemness (+), Progression (+), Metastasis (+), Drug resistance (+) Colon Colorectal cancer 284 , 287 ligand-dependent Ihh (-), Shh (+), Progression (+), Metastasis (+), Resistance (+) Pancreas Pancreatic cancer 289 – 291 , 294 ligand-dependent Shh (+), Smo (+), Gli1 (+) Initiation (+), Progression (+), Metastasis (+) Lung Lung cancer 299 , 304 , 305 , 514 ligand-dependent Shh (+), Gli (+) Progression (+), Stemness (+), Metastasis (+), Resistance (+) Blood Hematological malignancy 308 , 311 , 515 ligand-dependent Smo (+), Dhh (+), Gli1 (+) Radiation resistance (+), Stemness (+) Thyroid Thyroid cancers 320 , 324 , 516 ligand-dependent Shh (+), Ptch (+), Smo (+), Gli (+) Stemness (+), Progression (+), Resistance (+) Skin Basel cell carcinoma 327 , 329 , 335 ligand-independent Shh (+), Ptch1 (+), Gli1 (+) Progression (+), Resistance (+) Breast Triple negative breast cancer 341 , 342 , 345 , 346 ligand-dependent Smo (+), Gli1 (+), Shh (+) Progression (+), Metastasis (+), Resistance (+), Stemness (+) Muscle Rhabdomyosarcoma 351 , 357 ligand-dependent Gli1(+), Ptch1 (+) Progression (+), Stemness (+), Drug resistance (+) Stomach Gastric cancer 364 – 367 ligand-independent Shh (+), Gli1(+) Initiation (+), Progression (+), Drug resistance (+), Stemness (+)

Cancers in craniofacial complex

Squamous cell carcinomas account for more than 90% of oral malignant tumors and often begin with precancerous lesions. 197 Shh expressed in oral epithelial dysplasia and carcinoma in situ. 198 Also, Shh, Gli2, Smo, and Ptch are highly expressed in precancerous lesions of oral mucosa. 199 Higher expression levels of Ptch1, Smo, and Gli1 were found in oral squamous cell carcinoma (OSCC) cases when compared to nonneoplastic oral mucosa. Recent study demonstrated that Gli1 was present only in the nuclei of cancer-associated fibroblasts in OSCC, indicating that HH signaling is active in the progression of OSCC. 200 Furthermore, endophytic-type parenchyma of OSCC possessed a stronger expression of Shh and Ptch1 than exophytic-type parenchyma of OSCC. 201

HH signaling molecules are considered to be prognostic indicators in OSCC as overexpression of related proteins can be indicative to tumor size, metastatic potential, tumor recurrence and even to shorter overall survival. 202 , 203 HH signaling regulates cell proliferation in OSCC. 204 Several studies have investigated the molecular mechanisms on the invasion behavior of human OSCC. Ptch1 and Gli expression were found in the microvascular cells in the invasive front of OSCC. 205 Takabatake et al. reported that Ptch and CD31 double-positive blood vessels in the OSCC stroma might affect tumor angiogenesis in OSCC. 201 Also, Shh overexpression is correlated with cancer stem cell markers CD133 and Sox2 in OSCC specimens. 202 Shh might induce OSCC progression and invasion through prolonged half-life of activated leukocyte cell adhesion molecule (ALCAM) which is a transmembrane glycoprotein mediating cell adhesion and multiple other function of cancer cell. 206 An increased MMP-9 and downregulated epithelial cadherin (E-cadherin) expression caused by Shh signaling in OSCC might be responsible for the invasiveness and metastatic potential. 207

Odontogenic keratocysts (OKCs) accounts for 3.3–17.4% of all jaw cysts, of which neoplastic lesions often involve mandibles with a high clinical risk of recurrence. 208 , 209 Gorlin syndrome (GS) is a multisystem genetic disease caused by gain of function mutation in HH signaling pathway and manifests as multiple OKCs and basal cell carcinomas (BCCs). 209 , 210 The most common gene mutation for GS is Ptch1 while Ptch2, Smo and Sufu are also rare causative genes for GS. 211 Although multiple OKCs is a major symptom of GS, even patients with sporadic OKCs were suspected with an underestimated Ptch1 mutation rate. 212 Stojanov et al. demonstrated Ptch1 inactivating mutations accounts for 93% of sporadic OKCs. 213 Yu et al. indicated that mutations in the intracellular loop of Ptch1 might regulate Cyclin B1 in NBCCS-associated OKCs in a manner of noncanonical HH signaling pathway. 214 Ptch1 mutation leads to ligand-independent activation of Smo and subsequently upregulates HH signaling pathway target genes transcription.

Many studies concluded that the aberrant HH signaling pathway is active in the development of OKCs. 215 , 216 Grachtchouk et al. uncovered that elevated expression of HH target genes is detected in lower cell layers of cyst wall of human OKCs. 217 Besides, OKCs were found to express lower levels of Sufu gene and higher level of Smo, Ptch1, Cyclin D1 and Bcl2. 218 Syndromic OKCs were found to have a higher expression of HH signaling pathway protein than the sporadic OKCs. 219 Higher Smo expression was considered to be a risk factor of recurrence of OKCs. 220

Brain tumor

Brain tumor and other neoplasm in nervous system account for 1.6% new cases worldwide in 2020 and lead to more than 251,329 deaths. 185 Two types of malignant primary brain tumors including medulloblastoma (MB) and glioma were in close relationship with HH signaling pathway. 221 MB is a common aggressive malignant tumor in brain during childhood. 222 There are four subtypes of MB based on research on their molecular mechanism and clinical characteristics: Wnt-MB, Shh-MB, group 3 MB and group 4 MB. 223 The novel feature of Shh-MB is constitutive activation of the Shh signaling pathway.

HH signaling stimulates the proliferation of cerebellar granule neuron precursors (CGNPs) during cerebellar development, which lead to MB formation. 224 Researches have indicated that germline and somatic mutation of HH signaling pathway related components leads to MB and such mutation varies in different ages. 225 However, Ptch1 represents the most common oncogenic mutations in Shh-MB. 226 Nearly half of patients with Shh-MB harbored Ptch1 (45%) alterations while Smo (14%) and Sufu (8%) alterations were also detected. 227 Mouse model with conditional deletion of Ptch1 in CGNPs caused MB formation, suggesting that CGNPs play a central role in the origin of Shh-MB. 228 , 229 Astrocytes in the cerebellum perform important functions that support granule cell proliferation and migration in the physiological state while MB-associated astrocytes can secrete Shh ligand that helps maintain proliferation tumor cell in a Ptch1-independent manner. 230

HH signaling pathway has effect on multiple targets including Mycn, Snail1, Cyclin D1, Sox2, Sox9 and further influence cancer behavior as tumor growth and tumor cell proliferation during MB tumorigenesis. 231 Quiescent cells with a therapy-resistant characteristic can serve as a reservoir for relapse. Sox2, a neural stem cell marker, is recognized as a poor prognosis marker in human Shh-MB. In a mouse model of Shh-MB, cells expressing Sox2 accounts for a proportion of less than 5% of the total tumor cells but might serve as a reservoir for relapse. 232

Glioblastoma multiforme (GBM) is a common malignant brain tumor and account for 23% of all gliomas. 233 Given to characteristics of high invasiveness and drug resistance, GBM is a neoplasm with a dismal prognosis and an effective practical therapeutic approach remains under investigation. 234 Researchers have founded that HH signaling pathway is activated in human glioma cell lines, but not in cultured human astrocytes. 235 HH/Gli1 pathway affects the growth of glioma and glioma stem cells are thought to be generated by the population of Gli positive neural stem cells. Researchers reported that Gli1 and Gli2 expression is associated with grades III and IV gliomas with less survival. 236 The overall survival of patients with glioblastoma is decreased by upregulation of Shh based on data from the Cancer Genome Atlas glioblastoma. 237

Cell migration and proliferation in human GBM cell lines are associated with expression of connexin 43, an integral membrane protein within gap junctions, upon HH signaling pathway modulation. 238 Chang et al. enhances HH signaling pathway in GBM cells by recombinant human Shh N-terminal peptide, which increases the production of MMPs to promote cell migration and invasion through the PI3K/AKT pathway. 239 Overexpression of fms related tyrosine kinase 1 (FLT1) in GBM cells was related to the invasion and migration of tumor cells through HH signaling pathway. 240 Although, Shahi et al. reported a fainter expression of HH signaling pathway component in neuroblastoma (NB) than MB or glioblastoma. 241 Studies also reported that HH signaling pathway determines multiple biological behavior of neuroblastoma, 242 – 244 while several researchers proposed theories of a tumor-suppressive functions of HH signaling pathway in NB. 243 , 245

Renal cancer

Renal cell carcinoma (RCC) is the most common renal tumor, accounting for 80–85% of all renal cancers, as clear cell renal cell carcinoma (CRCC) is responsible for the vast majority of RCC. 246 , 247 Dormoy et al. reported HH signaling pathway components are expressed in human CRCC tumor samples, which participates in cell proliferation of CRCC cell lines and related tumor growth. Such reactivation of HH signaling pathway leads to regulation downstream gene transcription of Cyclin D1, PAX2, VEGF, and TGF-β. 248 The mRNA levels of Shh, Smo and Gli1 were higher in CRCC tissue compared with control kidney tissue in different degrees. 249 Gli3, Ptch1, Dhh, and Shh were highly expressed in in higher grade tumor as Dhh expression can be recognized as an independent predictor of CRCC survival. 250 Multiple studies show antitumor potential in human RCC by targeting HH signaling pathway. 251 , 252

HH signaling pathway influence aggressiveness of RCC. Recombinant Shh protein enhanced cell proliferation and suppressed the expression of E-cadherin in RCC cell lines, suggesting the essential role of EMT modulating by HH signaling pathway in RCC. 253 HH signaling pathway may interact with hypoxia-inducible factor 2α modulating the radiosensitivity of RCC. 254 Furukawa et al. suggested that Gli2 may be related to the underlying mechanism of drug resistance associated with tyrosine kinase inhibitor (TKI) inhibitors sunitinib in CRCC. 255

Prostate cancer

Prostate cancer (PCa) is the second most common cancer in male accounting for 14.1% new cases worldwide. 185 Paracrine signaling of HH signaling pathway is crucial to prostate development. 234 PCa originates from prostatic epithelia and epithelial-mesenchymal interaction plays an important role in PCa progression and metastasis. 256 , 257 Wilkinson et al. has shown the co-localization of Smo with primary cilia in prostatic fibroblasts and confirmed the activated HH signaling pathway in prostatic tumor microenvironment. 258 Also, Shh expression level was correlated with cell proliferation in PCa. HH signaling pathway blockade by cycloplamine, a selective inhibitor of Smo, significantly reduced the proliferation of PCa cell lines. 259 Enhanced expression of HH signaling pathway components was found in the cancer tissue than in the normal prostatic epithelial tissue, which was correlated with higher Gleason score and worse prognosis. 260 , 261 In animal models, overexpression of Hedgehog protein persistently in mutant mice accelerated the progression of prostatic intraepithelial neoplasia that led to PCa. Hyperplastic basal cells might be the true cellular origin of primary PCa. HH signaling pathway plays important roles in transforming normal prostate basal/stem cells into PCa stem cells. 262 In addition, inhibition of Shh signaling pathway showed potential for prevention of drug resistance such as zoledronic acid. 263

Liver tumor

HH signaling pathway is considered to play an essential role in liver organogenesis and hepatic tissue repair. 264 , 265 Importantly, HH signaling pathway is influential to multiple biological behaviors of liver tumor including hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CCC).

The most common malignant liver tumor is HCC. 185 Ptch1 was found overexpressed in HCC tissue compared with the surrounding non-neoplastic liver tissue. Moreover, increased expression of Smo and Gli1 was directly correlated to a large tumor size of HCC. 266 , 267 Ptch1 and Gli1 can be potential biomarkers for the recurrence of HCC and cumulative survival of HCC patients. 268 MMPs promote tumor metastasis by influencing extracellular matrix remodeling. Shh signaling pathway induces MMP-2 and MMP-9 production to promote invasiveness through FAK/AKT signaling in HCC. 269 HCC’s invasive behavior was attenuated by treatment with a Smo inhibitor which partially suppressed the expression of MMPs and Gli1/2. 270 In addition, target genes of HH signaling pathway such as EMT transcription factors were found overexpressed in poorly differentiated hepatoma cells in HCC. Activation of HH signaling pathway and related EMT factors might be responsible for the invasiveness and chemoresistance in poorly differentiated hepatoma cells. 271 , 272

A specific Gli inhibitor GANT-61 significantly suppressed HH signaling to reverse sorafenib resistance in CD44-positive HCC, suggesting HH signaling pathway can influence HCC drug resistance. 273 Further experiments by Zhou et al. confirmed that Gli1/2 binds to the promoter of transporter associated with antigen processing 1 (TAP1) gene, indicating that TAP1 is one of target genes of HH signaling pathway in HCC cell lines. RNAi targeting Gli or TAP1 can alleviating drug resistance. 274

CCC is a malignant tumor derived from biliary epithelial cells. According to different anatomical positions, it can be classified into intrahepatic, perihilar, and distal CCC, among which perihilar CCC represents about 50% of all cases. 275 Riedlinger et al. revealed a significant activation of HH signaling pathway in CCC samples and cell proliferation of CCC cells was significantly reduced by inhibiting HH signaling pathway. 276 The potential effectiveness was also confirmed in a CCC xenograft model that treatment with a combined therapy with BMS-833923 and gemcitabine inhibited tumor growth. Furthermore, HH signaling pathway components such as Gli1 and Gli2, are reliable prognostic factors for CCC. 277 , 278

Hypoxia influences multiple tumor biological behavior. Hypoxia inducible factor-1 (HIF-1) promotes cancer stemness and invasive behavior of CCC by modulating Shh, Smo and Gli1. 279 , 280 HH signaling pathway protein might promote the interaction between cancer cell and stromal cell and eventually further promotes cancer progression. Coculture of CCC cells with hepatic stellate cell line Lx-2 increased cancer cell migration and invasion. 281 CCC cells in conventional and hypoxic conditions have been observed to promote tumor-associated macrophage polarization and TGF-β1 secretion via paracrine Shh ligands, thereby promoting CCC cell growth, metastasis and endoplasmic reticulum homeostasis via TGF-β1. 282

Colorectal cancers

Among all malignant tumors, colorectal cancer (CRC) ranks third in the world. 185 HH signaling pathway in the gastrointestinal tract relies mainly on paracrine secretion for completion. In mouse models, the overexpression of Shh ligands provided advantages in growth to tumor cells by activating HH signaling pathway in the surrounding stroma. 196 Further studies have shown that Shh ligands are upregulated in CRC in order to activate the stromal HH signaling pathway, while stromal downstream genes, such as Gli1 and Hhip expression, are decreased. 283 This could explain the negative results and Shh ligand overexpression that were evident in clinical trials involving vismodegib for CRC. Several studies have indicated that the downregulation of Ihh can be observed as an early event in the formation of CRC. 284 , 285 Ihh is mainly expressed in the stromal tissue of the colon, and its high expression level has been described to inhibit the development of CRC. 283 In a mutant mouse model, colorectal epithelial cells were shown to secrete Ihh to maintain the intestinal stromal phenotype, which was essential to adenoma development, suggesting that Ihh could influence colorectal malignancies in a variety of manners. 286 Hypoxic environments can induce the binding of HIF-1α produced by tumor cells and TGF-β2 secreted by cancer-associated fibroblasts to activate Gli2 expression in CRC cells, thus leading to elevated resistance of CRC cells to chemotherapy. 287

Pancreatic cancer

Overall 5-year survival of pancreatic cancer is below 10%. 288 Shh is aberrantly expressed in pancreatic intraepithelial neoplasia and HH signaling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. 289 High expression of Shh and Gli1 was an independent prognostic factor for worse survival of patients with pancreatic ductal adenocarcinoma (PDAC). 290 Moreover, pancreatic cancer-associated fibroblasts show overexpression of Smo that lead to activation of HH signaling pathway. 291

HH signaling pathway influences multiple tumor cell behavior in pancreatic cancer through regulating Gli1 expression. Gli1 expression is essential for PDAC cell survival by facilitating the migration and invasion of cells by promoting EMT. S100A4 is an EMT indicator protein and might be an essential target gene mediated by Gli1 in pancreatic cancer. 292 , 293 However, Lee et al. proposed that stromal response to HH signaling pathway is protective against PDAC and that HH signaling pathway activated by SAG21k can decelerate tumorigenesis. 294 Perineural invasion is an important characteristic of pancreatic cancer with an incidence of 70–100%. Cancer cells invade into peripheral nerves in pancreatic tissue and are considered to be associated with poor tumor prognosis and cancer pain. 295 , 296 Moreover, overexpression of Shh activates HH signaling pathway in pancreatic stellate cells in the tumor stroma which is not only essential for tumor growth but also responsible for the nerve invasion in cancer. 297

Lung cancer

Similar to many cancers, HH signaling pathway is also important for the prediction of lung cancer prognosis. 298 Inhibition of Shh signaling by cycloplamine induces a significant decrease in the proliferation of Non-Small-Cell-Lung-Cancer (NSCLC) cells mediated by Gli through regulation of cyclin expression. Moreover, increased Shh expression in NSCLC might be related to cancer progression mediated by cancer stroma-associated fibroblast. 299

Researchers found that in patients with lung adenocarcinomas tumors and lung squamous cell carcinomas had higher Gli expression, accompanied by significantly lower expression of an EMT marker E-Cadherin. Inhibition of HH signaling pathway in vivo decreased tumor growth and induced E-Cadherin expression. 300 , 301 Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are widely used as first line therapy for NSCLC. Upregulation of HH signaling pathway resulted in EGFR-TKIs resistance by EMT induction. Blockade of HH signaling increased sensitivity to EGFR-TKIs in NSCLC cells. 302 HH signaling pathway drives lung adenocarcinoma (LAC) cells growth under stress conditions such as serum-starvation. 303 Moreover, microRNA (miRNA) disorders might be related to cell cisplatin resistance in LAC through targeting Gli2. 304 Besides, researchers found that Shh + NSCLC cells produced full-length Shh protein on the membranes of these cells. Shh + cells exhibited chemo-resistance and showed proliferation and migration stimulatory effect on Shh - cells in a paracrine manner. 305

Hematological malignancy

It has been found that HH components are aberrantly activated in a variety of hematological malignancies including multiple biological behavior. HH signaling pathway was upregulated in CD34 + hematopoietic cells from patients with chronic myelomonocytic leukemia (CML). 306 , 307 HH signaling pathway is increased in BCR-ABL + progenitor cells in CML through enhanced expression of Smo. Smo is responsible for the downregulation of microRNA-326 in patient with CML. 308 , 309 Inhibiting Gli2 abolishes dormancy in human leukemia stem cells. 310

Gli expression can be recognized as a prognostic indicator for acute myeloid leukemia (AML) and elevated Dhh plasma level can be detected in AML patient. 311 In a murine model of myelodysplastic syndrome (MDS), HH signaling pathway activation led to leukemic transformation to AML by acquiring self-renewal potential. 312 Stromal cells show potential of supporting activity for proliferation of leukemic cells and the expression of human Hhip in AML/MDS-derived stromal cells was markedly lower than stromal cells from healthy individuals. 313 HH/Gli-1 also plays a key role in resistance to radiation, and that inhibition by LDE225 precipitates a radiation-resistant cell line overcoming radioresistance. 314 HH signaling pathway has important impact on B-cell in chronic lymphoblastic leukemia, acute lymphoblastic leukemia (ALL) and multiple myeloma. 315 – 317 HH signaling pathway is associated with progression of these diseases. 318 Targeting HH signaling pathway holds promising therapeutic effects.

Thyroid cancer

A total of 80% of thyroid cancers occur as papillary thyroid carcinomas (PTCs). 319 A majority of Thyroid tumor specimens are positive for HH signaling pathway component (Shh, Ptch, Smo, and Gli) while inhibition of HH signaling pathway reduced proliferation of thyroid tumor cell lines. 320 Shh enhances cell motility and invasiveness of anaplastic thyroid carcinomas. 321 Moreover, Shh signaling pathway is important to PTCs occurrence and progression. 322 , 323 It also regulates CSC self-renewal and radiosensitivity in anaplastic thyroid carcinomas cell lines by Snail expression. 324 Ma et al. proposed that the loss of primary cilia has been linked to the malignant transformation in thyrocyte. 325

Basal cell carcinoma

As the most common skin malignant tumor, BCC is most likely to occur in the skin of head and face. 326 Multiple BCC is a major symptom of Gorlin syndrome. 90% of sporadic BCC cases carry somatic mutations in Ptch, others have gain of-function mutations in Smo, leading to over-activation of the pathway. 327 , 328 Overexpression of Ptch1 and Gli1 were observed in BCC compared with normal epidermal tissue and enhanced Shh immunoexpression was found in the aggressive BCC. 329 , 330 Interestingly, Gli1 was specifically upregulated in BCC, while the other skin malignancies such as squamous cell carcinoma showed no Gli1 expression. 331

Intrafollicular epidermal stem cells are reported to induce BCC formation through HH signaling pathway due to their enhanced self-renewing ability. 332 The tumor epithelium of human BCC with Smo inhibitor resistance possesses reduced primary cilia. Loss of primary cilia might be related to HH signaling pathway inactivation and upregulated RAS/MAPK pathway in resistant BCCs. 333 A lower cilia count in the primary lesion might be correlated with BCC recurrence according to a preliminary study. 334 Whitson et al. reported non-canonical hedgehog pathway activation also drives drug resistance of Smo inhibitor in BCC. 335

Triple negative breast cancer

There were 2.3 million new cases of female breast cancer (BC) in 2020, surpassing lung cancer as the most common cancer worldwide. 185 Among all BC subtypes, 10% are triple negative breast cancer (TNBC). Poor prognosis and the lack of efficient targeted therapy make TNBC treatment most challenging.

Multiple studies have shown that HH signaling pathway plays an essential role in normal mammary gland development. 336 HH signaling pathway mediates ductal morphogenesis of the mammary gland during puberty and remains downregulated in normal adult mammary tissue. 336 , 337

HH signaling pathway in relation to the aggressive biological behavior of TNBC, including cancer migration, invasion and angiogenesis, has also been discussed. 338 Somatic mutations of HH signaling pathway components have been shown to be relatively rare in BC, where ligand-dependent HH signaling pathway activation played a more fundamental role in the pathogenesis of TNBC. 339 Moreover, expression of Shh, Dhh, Ptch1, Gli1 has been observed to be upregulated in BC tumor tissue. 340 Smo and Gli1 in TNBC tissue is also significantly increased compared to those of non-triple-negative BC. 341 Furthermore, TNBC patients with higher Shh expression have worse overall survival. 342

HH signaling pathway promotes TNBC progression in an autocrine manner, while promoting tumor vascularization via regulation of vascular endothelial growth factor receptor 2 (VEGFR2) expression in a paracrine manner. 343 Another possible mechanism of TNBC chemoresistance is HH signaling pathway upregulated ATP binding cassette (ABC) transporters and other target genes. 338 TNBC cells may also harbor dysfunctional stemness pathways compared to non-triple-negative BC cells. 338 TNBC associated fibroblasts can activate HH signaling pathway in a paracrine manner and enhance tumor cell growth. 344 In addition, HH-activated CAFs have been shown to form a niche for chemo-resistant TNBC stem cells and target HH-activated CAFs via Smo inhibitors, which benefits patients suffering from TNBC. 345 Exposure to chemotherapeutics agents of TNBC cell lines results in the release of Shh and HH signaling pathway activation, leading to an increase in the stemness marker of TNBC stem cells, which may explain the chemoresistance and recurrence of TNBC. 346 The above evidence may illustrate one possible way that could relate to the aggressiveness and difficulty in treating TNBC by HH signaling pathway.

Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is known to be the most common type of soft tissue sarcoma in children whose cells tend to undergo myogenic differentiation. 347 Two major subtypes of this condition are embryonal subtype of RMS (ERMS) and alveolar subtype of RMS (ARMS). 348

The relationship between RMS and HH signaling pathway was first identified in mice heterozygous for Ptch1 as these mutants exhibited a high incidence of ERMS. 349 The consistent activation of the HH pathway has been associated with RMS, though there have been relatively few RMS cases in patients with Gorlin syndrome. 211 According to the Children’s Oncology Group, 18% of patients with fusion-negative RMS harbor a mutation in HH signaling pathway. 350

Controversy is still prevalent pertaining to the exact mechanism of the constitutive activation of HH signaling pathway in RMS. Overexpression of HH signaling pathway components, such as Gli1 and Ptch1, has been detected in RMS patient samples and human RMS cell lines. 351 However, activating mutations of HH signaling pathway reported to date only account for a small subset of patients. 347 A particular study proposed a different model of RMS in HH signaling pathway activation, where a wide distribution of Dhh and Ihh ligands were detected by immunohistology in RMS samples, in which Shh was only found to be expressed in a small set of RMS cell lines. These findings demonstrated the potential mechanism of the ligand-dependent activation of HH signaling pathway in RMS. 352 Hatley et al. utilized aP2-Cre; Smo M2 /+ mutant mice and discovered that the activated HH signaling pathway in the adipose lineage led to ERMS in mice. 353 Fu et al. reported that primary cilia play a central role in muscle differentiation. Either ciliogenesis or HH signaling pathway are dysregulated in RMS. 354

Targeting HH signaling pathway in RMS has demonstrated therapeutic potential in in vitro studies, and its inhibition contributes to the suppression of cell invasion and self-renewal in RMS cell lines. 355 , 356 Meanwhile, upregulation of Gli1 contributes to drug resistance. 357

However, the pathogenesis of RMS as well as the oncogenic role of HH signaling pathway remains unclear, and further studies should be urgently conducted in order to develop effective treatment options for RMS

Gastric cancer

Gastric cancer (GC) deaths ranks fourth among all cancers and has led to more than 760,000 deaths in 2020. 185 Although the incidence of GC decreases annually, gastric cancer continues to be fatal, with a sharp shortened survival. 358

In stomach, HH signaling pathway is essential for differentiation and maturation of gastric epithelial cells under physiological conditions. 359 Shh is highly expressed in gastric parietal cells for gastric acid and gastrin production, illustrating that HH signaling pathway is indispensable for normal digestive function. 360

HH signaling pathway links progression from chronic inflammation to cancerous lesions. 361 Helicobacter pylori ( H pylori ) infection is one of the main causes of chronic gastritis and is a significant risk factor for gastric cancer. Multiple studies have reported that chronic H pylori infection can interfere in the balance of HH pathway activity within gastric tissue. 360 H pylori may also contribute to gastric atrophy and intestinal metaplasia for increased potential of tumorigenesis. 362 Mice with parietal cell-specific deletion of Shh were not observed to develop gastritis when infected by H pylori , and Shh in gastric mucosa was considered to act as a chemoattractant for macrophages. 363

Shh has been found to be overexpressed in resected GC samples compared to that of adjacent normal tissue. 364 Specifically, Shh expressing in H pylori positive patients with early GC was noted to be significantly higher than H pylori negative controls. 365 The increased expression of Shh and Gli1 was also shown to be significantly correlated with tumor staging and tumor aggressiveness, suggesting a worse overall survival for patients suffering from GC. 193 , 366

Shh promotes gastric cancer cell proliferation and the survival of lines, which suggests an autocrine progression of gastric cancer. It also regulates gastric cancer migration and invasion of gastric cancer cell lines through EMT.

Shh-Gli1 signaling was activated in CD44 + gastric cancer stem cells, which was responsible for drug resistance in advanced GC. Moreover, Gli interacts with the promoter of ABCG2 and regulates its expression in gastric cancer stem cells. 367 Accordingly, targeting HH signaling pathway may improve GC chemosensitivity. 368 , 369 Koh et al. investigated PDL-1 expression mediated by Gli in gastric cancer organoids, which may relate to immune evasion in GC. 370

A brief summary on HH signaling pathway in cancer

HH signaling pathway participates in multiple functions in a variety of tumors. According to immunohistology, early exploration of HH signaling pathway was concentrated on the expression and distribution of the HH pathway components in tumor tissue. One potential reason for controversies in early studies that examined the expression patterns of HH signaling pathway proteins in cancer could be differential tumor samples analyzed. 371 In light of the rapid understanding of tumor biology, additional features of HH signaling-associated cancers have been determined. Cancer stem cells and the hedgehog pathway are closely related to cancer relapse and cancer resistance to anticancer therapy. In addition, the mechanism of HH signaling pathway activation in cancer is multifactorial, demonstrating that canonical pathway activation and noncanonical pathway activation may exist in a single form of cancer. 372 Similarly, ligand-dependent and ligand-independent activation may promote cancer progression cooperatively. Therefore, further studies should focus on the precise mechanism of HH signaling pathway in cancer for better therapeutic targets.

Targeted therapies of HH signaling in cancers

Introduction of targeted therapies

Recent breakthroughs have revealed the carcinogenic function of HH signaling pathway, which makes it an interesting target for cancer treatment. Drugs related to HH signaling pathway target Hhat, Shh, Ptch, Smo, Sufu and Gli1 (Fig. 5 ). These drugs targeting HH signal transduction can be divided into small molecule inhibitors, natural chemicals, lncRNAs and monoclonal antibodies. Among them, small molecule inhibitors are the most widely studied, usually referring to chemical compounds with molecular weight less than 1 kDa. These drugs have significant advantages: (1) small molecular weight brings more obvious permeability to tissues and cells; (2) there are various forms of drug delivery; (3) oral tolerance and bioavailability are good. Fig. 5 Inhibitors targeting HH signaling pathway. In this figure, we mainly show the inhibitors targeting HH signaling pathway, classified according to the properties of the compounds, and the inhibitors in ongoing or completed clinical trials are shown in red. Approved drugs are individually identified, including their indications. BCC basal cell carcinomas, AML acute myeloid leukemia, APL acute promyelocytic leukemia

In 2000, the first drug targeting HH signaling pathway, arsenic trioxide (ATO), was approved for the treatment of acute promyelocytic leukemia (APL). 373 ATO not only inhibits HH signaling pathway, but also targets other signaling that involved in the development and progression of APL. The first Food and Drug Administration (FDA) approved drug specifically designed to target HH signaling pathway is vismodegib (GDC-449), which was approved for the treatment of BCC in 2012. 374 Since then, sonidegib and glasdegib have been approved for clinical treatment of cancer. 375 , 376 Although vismodegib and sonidegib have achieved satisfactory outcome in the treatment of locally advanced or metastatic BCC, frequent Smo mutations lead to increased drug resistance. 377 Therefore, recent studies have revealed that new HH signaling pathway inhibitors and reasonable multi target drugs are applied together to solve this problem, including taladegib, LEQ-506 and TAK-441, which are not sensitive to drug-resistant D473H mutations. 378 – 380 In addition, some studies on Hhat, Shh and Gli1 inhibitors are also expected to inhibit Smo resistant cells.

Hhat inhibitor

Hhat catalyzes the completion of palmitoylation of HH proteins to maintain their stability and normal activity. 381 Inhibitors targeting Hhat may therefore block HH protein-mediated pathway activation. Current inhibitor targeting Hhat was RU-SKI 43. Petrova et al. carried out a high throughput screen using a peptide-based assay and identified Hhat specific inhibition by RU-SKI 43 both intracellularly and in vitro. 382 They further investigated the potential effect of RU-SKI 43 in cancer. The results suggested that RU-SKI 43 was able to reduce Gli1 activation, Akt and mTOR pathway activity and tumor growth in vitro in pancreatic cancer cell proliferation and in vivo in xenograft models by inhibiting Hhat. 383 It should be noted that the inhibition effect of RU-SKI 43 was not mediated through Shh protein. 383 Another study showed similar observations that RU-SKI 43 treatment reduced the proliferation of estrogen receptor positive breast cancer cells, showing a dose-dependent effect. 384 Overexpression of Hhat protein was able to rescue this inhibition, but the addition of exogenous recombinant Shh protein did not. 384 The lack of Hhat inhibitor studies may be due to the need to use radiolabeled fatty acid substrates to measure activity, which has limitations in terms of throughput, cost and safety. 385 Recently, Andrei et al. proposed an acylation-coupled lipophilic polarization induction assay. They applied this method to discover the potent Hhat inhibitor IMP-1575. 385 , 386 Future studies will be needed to reveal the role of IMP-1575 in anticancer therapy.

Shh inhibitor

Shh proteins bind to and inhibit Ptch1 receptor, which could unblock Ptch1 for Smo proteins and cause typical HH signaling pathway. Inhibitors targeting Shh proteins may therefore block Shh protein-mediated signaling pathway activation. Inhibitors targeting Shh include 5E1, Hedgehog-interacting protein (Hhip) and Robotnikinin.

5E1

5E1 is a monoclonal antibody targeting Shh and blocks HH signaling pathway by competing with Ptch1 for the Shh binding site. 387 Treatment of colorectal cancer cell lines with 5E1 reduced the expression of HH signaling pathway target genes (Gli1, Ptch1, Hip1, Muc5ac) as well as cell cycle protein D1 and mediated the reacquisition of epithelial-like features in cells. 388 5E1 was also shown to inhibit the self-renewal capacity and chemoresistance of gastric cancer stem cells, demonstrating a potential role for 5E1 in enhancing chemotherapeutic sensitivity. 389 In the non-Smo protein-mediated HH signaling pathway, 5E1 may have a more satisfactory effect. Both cyclopamine and 5E1 could inhibit chronic lymphocytic leukemia (CLL) cells in B-CLL patients. 390 Stromal cells could induce activation of the paracrine pathway and activated ERK directly via Ptch1 receptor in CLL cells without Smo. 390 In this case, cyclopamine treatment was suboptimal, while 5E1 could completely eliminate ERK phosphorylation. 390

Hhip

Hhip is a negative regulator of HH signaling pathway that prevents Ptch1 from binding Shh by binding the cholesterol fraction covalently linked to Shh through the N-terminal. 391 Abnormal expression of Hhip has been associated with cancer development. For example, hypermethylation of the Hhip gene promoter has been found in several tumor cell lines, including HCC, pancreatic cancer, MB, and various gastrointestinal tumors. 392 – 395 Down-regulation of Hhip expression using siRNA resulted in a significant increase in colon cancer cell growth and invasion in vitro. 395 Therefore, adjustment of Hhip level allows regulation of cancer development. Yu et al. used a lentiviral vector to deliver Hhip. The result showed that gastric cancer cells in the Hhip group had reduced proliferation, migration and invasion compared to the control. 396 Interestingly, Hhip overexpression significantly reduced its de novo promoter methylation level in gastric cancer cells. 396

Robotnikinin

Robotnikinin is a small molecule that targets Shh-N protein. It has the following features: inhibits HH signaling pathway in a concentration dependent manner; does not show inhibitory activity in the absence of Ptch1 receptors; does not compete with cyclopamine. 397 Robotnikinin reduced Gli2 mRNA levels in human keratin forming cells and in primary human synthetic skin tissue. 397 There is currently lack of other studies revealing the potential application of robotnikinin in the treatment of cancer.

Ptch activator

Ptch is an inhibitor of HH signaling pathway. Without Shh ligand, Ptch plays a regulatory role by inhibiting the Smo protein. 398 Ptch protein silencing or gene deletion is related to the development of many cancers, such as odontogenic keratocyst, BCC and plexiform fibromyxoma. 213 , 399 , 400 Therefore, activators targeting Ptch can prevent cancer development by inhibiting Smo protein. At present, some natural compounds have been found to increase Ptch1 expression, for example, the combination of epigallocatechin gallery (EGCG) and theaflavin (TF) can reduce the expression of Gli1 and Smo while increase the expression of Ptch1 in mouse liver cancer cells. 401

Smo inhibitor

Within HH signaling pathway, Smo protein is often utilized as the drug target because of (1) the ability to transduce downstream signaling pathways in cancers with a loss of function of Ptch1, (2) cancer-causing capacity in the presence of aberrant expression, and (3) the hydrophobic structural transmembrane helical domain capable of binding a variety of small-molecule drugs. The inhibitors targeting Smo mainly include cyclopamine, and cyclopamine derivatives such as vismodegib, sonidegib, etc.

Cyclopamine

Cyclopamine is a steroidal alkaloid metabolite produced by Veratrum californicum , which has been shown to bind and inhibit the activity of Smo proteins. 402 , 403 Cyclopamine may inhibit the development of several cancers by affecting HH signaling pathway. Cyclopamine is able to block HH signaling pathway in vitro, which in turn affects the aggressiveness and motility of human HCC cells. 404 , 405 On the other hand, in an in vivo study, Jeng et al. observed a statistically significant reduction in tumor size in mice with HCC (0.152 ± 0.219 cm 2 vs. 0.003 ± 0.009 cm 2 ) following a 2-week cyclopamine injection at a dose of 30 mg/kg/day. 406 Cyclopamine has also been shown to inhibit the self-renewal and invasive capacity of cancer stem cells in pancreatic cancer and glioblastoma. 407 , 408 Unfortunately, the poor oral bioavailability and specificity of cyclopamine limit its applications. 409 Under this circumstance, semi-synthetic cyclopamine derivatives such as vismodegib, sonidegib and saridegib have been developed, which show better oral bioavailability and perform well in several clinical trials. Of note, cyclopamine may still function as an anti-cancer agent for sensitization to radiotherapy. For instance, Tsai et al. showed that cyclopamine in combination with radiation therapy resulted in a 67% reduction in the average size of in situ tumors compared to radiation therapy alone. 410

Vismodegib (GDC-0449)

Vismodegib, a second generation cyclopamine derivative, was approved by the FDA in 2012 as the first Shh inhibitor for BCC treatment. 374 , 411 Vismodegib achieved satisfactory results in clinical trials in patients with locally advanced and metastatic BCC. After 21 months of daily oral administration of 150 mg vismodegib, the objective remission rate was 47.6% for locally advanced BCC and 33.3% for metastatic BCC, with a median remission and progression-free survival of 9.5 months months. 412 , 413 Several phase I and phase II studies have investigated the use of vismodegib in detail, for instance, vismodegib in the treatment of TNBC, multiple BCC, recurrent/refractory MB, and keratinized cystic odontogenic tumors with significant therapeutic benefit. 345 , 414 – 416 In 2016, Jacobsen et al. evaluated the effect of vismodegib for BCC by meta analysis. 417 Data from eight studies with a total of 744 patients showed that: objective response to vismodegib for locally advanced BCC had a weighted average of 64.7% and complete response averaged 31.1%. The objective response for metastatic BCC was 33.6% and complete response averaged 3.9%. 417 This meta-analysis showed that vismodegib was identified to have a significant and consistent effect on the median duration of therapy (35.8 weeks) of locally advanced BCC and metastatic BCC. Vismodegib, on the other hand, was not effective in the treatment of metastatic pancreatic cancer, lymphoma, chronic leukemia, and advanced osteosarcoma. 418 – 420 Therefore, more comprehensive clinical trials are needed to validate vismodegib in different populations. Several clinical trials of vismodegib are currently underway as monotherapy as well as in combination therapy for leukemia, meningioma and chondrosarcoma (Table 3 ). Adverse events associated with vismodegib include muscle cramps, taste disturbances, weight loss, hair loss, and weakness. 421 These conditions often subside spontaneously within 4 weeks, but the management of adverse reactions should not be neglected. 421 Table 3 Summary of drugs in clinical trials targeting canonical HH signaling in cancer Drugs Target protein NCT N Status Phase Cancer Vismodegib Vismodegib Smo NCT02436408 35 Completed Phase IV BCC NCT01201915 74 Completed Phase II BCC NCT01267955 45 Active Phase II Chondrosarcoma NCT01367665 1232 Completed Phase II BCC NCT01700049 28 Completed Phase II BCC NCT01815840 229 Completed Phase II BCC NCT00739661 104 Completed Phase II OC NCT02366312 2 Completed Phase II KCOT NCT03052478 10 Completed Phase II Stomach neoplasms Vismodegib/Chemotherapy/Other Smo NCT01878617 660 Active Phase II MB Vismodegib/GSK2256098/Capivasertib/Abemaciclib Smo/ FAK/ AKT / CDK NCT02523014 124 Recruiting Phase II Progressive meningiomas Vismodegib+ Chemotherapy Smo NCT01835626 24 Completed Phase II Locally advanced BCC; Skin cancer; CM Vismodegib+ Chemotherapy Smo NCT02694224 40 Recruiting Phase II TNBC Vismodegib+ Pembrolizumab Smo + PD-1 NCT02690948 16 Completed Phase I-II Metastatic or unresectable BCC Vismodegib+ Ribavirin+ Decitabine Smo NCT02073838 23 Completed Phase II AML Vismodegib/Other targeted drugs Smo NCT02091141 670 Completed Phase II Neoplasms Vismodegib/Other targeted drugs Smo NCT03158389 350 Recruiting Phase I-II Glioblastoma Vismodegib/Other targeted drugs Smo NCT03297606 720 Recruiting Phase II NHL; MM; Advanced solid tumors Vismodegib+ Bevacizumab Smo + VEGF NCT00636610 199 Completed Phase II Metastatic CRC Vismodegib+ Gemcitabine Hydrochloride Smo NCT01064622 118 Completed Phase I-II PC Vismodegib+ Gemcitabine Hydrochloride+ nab-Paclitaxel Smo NCT01088815 98 Completed Phase II PC Vismodegib+ RO4929097 Smo + Gamma-Secretase NCT01154452 78 Completed Phase I-II Advanced or metastatic sarcoma Vismodegib+ Gemcitabine Hydrochloride Smo NCT01195415 25 Completed Phase II PC Sonidegib Sonidegib Smo NCT03534947 10 Recruiting Phase II BCC NCT01708174 22 Completed Phase II MB NCT00961896 18 Completed Phase II BCNS NCT01125800 76 Completed Phase I-II MB NCT01350115 10 Completed Phase II BCNS Sonidegib+ Lenalidomide Smo + Cereblon NCT02086552 28 Completed Phase II Recurrent/refractory PCM Sonidegib+ Ribociclib Smo + CDK4/6 NCT03434262 68 Active Phase I Refractory or recurrent MB Sonidegib+ Radiotherapy+Chemotherapy Smo NCT04402073 205 Recruiting Phase II MB Saridegib Saridegib Smo NCT02762084 17 Completed Phase II BCNS NCT02828111 36 Completed Phase II BCC Saridegib+ Gemcitabine Smo NCT01130142 122 Completed Phase I-II PC Glasdegib Glasdegib Smo NCT01841333 31 Completed Phase II AML NCT01286467 23 Completed Phase I Solid tumors NCT01842646 35 Completed Phase II MDS; CML Glasdegib+ Temozolomide Oral Capsule Smo NCT03466450 75 Active Phase I-II Glioblastoma Glasdegib+ Chemotherapy Smo NCT01546038 255 Completed Phase II AML Glasdegib+ Other targeted drugs Smo NCT03390296 50 Completed Phase I-II AML Glasdegib+ Azacitidine Smo NCT04842604 15 Completed Phase III AML; MDS; CML Taladegib Taladegib+ Chemotherapy Smo NCT02784795 94 Completed Phase I Solid tumor; BC; CC; CCC; STS TAK-441 TAK-441 Smo NCT01204073 34 Completed Phase I Nonhematologic malignancies Itraconazole Itraconazole Smo NCT01108094 29 Completed Phase II BCC NCT01787331 21 Completed Phase II Prostate adenocarcinoma NCT02354261 38 Completed Phase II BCC Itraconazole+ AZD9291 Smo + EGFR NCT02157883 39 Completed Phase I Advanced/inoperable NSCLC Itraconazole+ volasertib Smo + PLK1 NCT01772563 28 Completed Phase I Neoplasms Itraconazole+ Other drugs Smo NCT02770378 10 Completed Phase I Glioblastoma Vitamin D3 Vitamin D3 Smo NCT02553447 197 Active Phase I CLL; NHL Vitamin D3+ Photodynamic Therapy Smo NCT03483441 37 Active Phase I BCC; BCNS Vitamin D+ Rituximab Smo + CD20 NCT03078855 211 Active Phase III NHL ATO ATO + GO Gli + CD33 NCT00274781 30 Completed Phase II Advanced MDS ATO + GO + ATRA Gli + CD33 NCT01409161 151 Recruiting Phase II APML BCC Basal cell carcinoma, OC ovarian cancer, BCNS Basal cell nevus syndrome, MB medulloblastoma, KCOT keratocystic odontogenic tumor, CRC colorectal cancer, CM cutaneous malignancy, TNBC triple negative breast cancer, AML acute myeloid leukemia, PCM plasma cell myeloma, NHL non-Hodgkin lymphoma, PC pancreatic cancer, MM multiple myeloma, CML chronic myelomonocytic leukemia, MDS myelodysplastic syndrome, EC esophageal cancer, BC breast cancer, CCC cholangiocarcinoma, CC colon cancer, STS soft tissue sarcoma, NSCLC non-small cell lung cancer, CLL chronic lymphocytic leukemia, APML acute promyelocytic leukemia

Sonidegib (LDE225)

Sonidegib (LDE225) is a Smo antagonist found by high-throughput screening in vitro. 422 In vivo and in vitro studies found that sonidegib can effectively reduce epithelial mesenchymal transformation and invasion potential of various types of cancer, such as glioblastoma, PCa and renal cell carcinoma. 251 , 423 , 424 A phase II clinical trial proved that sonidegib was administered with 200 mg and 800 mg respectively, the objective remission rates of locally advanced BCC were 57.6% and 43.8%, metastatic BCC were 7.7% and 17.4%, and the incidence of adverse events in the 200 mg group was lower. 425 Another phase II clinical trial yielded the similar results. 426 Based on this, FDA approved sonidegib for the treatment of locally advanced BCC in 2015. 375 A meta-analysis of Shh inhibitors for BCC included 22 studies from 2009–2022 and showed overall response rates (ORRs) of 50.1% for sonidegib compared with 68.5% for vismodegib. 427 This indicates that the majority of patients receiving sonidegib and vismodegib achieved promising treatment outcomes. In recent years, some clinical studies have focused on applying sonidegib to other cancers, such as MB, ovarian cancer, breast cancer, etc. 428 – 430 Sonidegib showed ideal therapeutic effect and safety in the treatment of these cancers. Sonidegib related adverse events included muscle spasms, taste disorders, nausea, alopecia, and elevated creatine kinase levels. 431 These reactions are often mild, but long-term adverse reactions may also lead to the decline of patients’ quality of life and drug withdrawal. 431 Compared with vismodegib, patients receiving sonidegib treatment had lower overall adverse events and occurred more slowly. 432 At present, several clinical trials of sonidegib as a single therapy and a combination therapy are under way, mainly for the treatment of MB (Table 3 ).

Saridegib (patidegib, IPI-926)

Saridegib (patidigib, IPI-926) is a semi synthetic derivative of cycloparamide in Smo inhibitor, which has significantly improved drug characteristics, efficacy and good pharmacokinetic characteristics. 433 In vivo and in vitro studies show that saridegib can effectively inhibit the proliferation and invasion of chondrosarcoma, serous ovarian cancer, osteosarcoma, acute lymphocytic leukemia and other cancer. 434 – 437 It is worth noting that saridegib also shows a prominent inhibitory effect on the drug-resistant cells obtained by D473H point mutation after the treatment of MB with vismodegib. 438 A phase I study used saridegib and FOLFIRINO (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) to treat 15 patients with advanced pancreatic cancer. Four out of five patients treated with saridegib monotherapy observed a continuous decrease in CA19-9 (26.9–97.7%). 439 In addition, saridegib and cetuximab also showed anti-tumor activity in the phase I study on the treatment of recurrent/metastatic head and neck squamous cell carcinoma. 440 The common adverse reactions of saridegib treatment are fatigue, nausea, muscle spasm, liver dysfunction and alopecia. 441 These adverse reactions are similar to other HH signaling pathway inhibitors and may be caused by inhibition of the same pathway.

Glasdegib (PF-04449913)

Glasdegib is a selective small molecule inhibitor that binds to Smo protein. 442 A randomized phase II clinical trial showed that compared with cytarabine alone, glasdegib combined with cytarabine can effectively treat AML patients who are not suitable for intensive chemotherapy or have high-risk MDS (median survival, 8.8 vs 4.9 months; 12 month survival, 59.8% vs 38.2%), with better safety and tolerance. 443 Based on this study, FDA approved the combined treatment of glasdegib and low-dose cytarabine for newly diagnosed AML patients who are not suitable for intensive induction chemotherapy in 2018. 376 In addition, the phase I study of glasdegib in patients with advanced solid tumors shows that it can keep the patient’s condition stable for a long time. 444 At present, glasdegib is conducting further clinical trials, including evaluating whether it can effectively treat AML, MDS or CML patients who have not been treated before with or without cytosine arabinoside ( NCT04842604 ) and whether the combination of glasdegib and temozolomide can effectively treat glioblastoma ( NCT03466450 ). Further clinical research will help to reveal the safety and effectiveness of glasdegib in cancer treatment.

Taladegib (LY2940680)

Taladegib binds to the extracellular end of the Smo transmembrane spiral bundle to inhibit the transmission of HH signal transduction. 58 The effect of taladegib is not affected by D473 mutation, and it can effectively treat tumor cells resistant to vismodegib. 378 Phase I clinical trial proved that taladegib has acceptable safety in the treatment of locally advanced and metastatic BCC patients. The common adverse events are taste disorder, fatigue, nausea and muscle spasm. 445 It is worth noting that another phase I study showed that Notch inhibitor crenigacestat combined with taladegib was poorly tolerated in the treatment of patients with advanced or metastatic solid tumors, showing disappointing clinical efficacy. 446 The reason why the combination therapy is not ideal may be due to the heterogeneity of the patient population or the history of systemic therapy. 446 Further research on taladegib single drug therapy or combination therapy will fully reveal its safety and therapeutic effect.

XL-139 (BMS-833923)

XL-139 (BMS-833923) is a Smo inhibitor, which has been proved to inhibit tumor in many in vitro and in vivo studies. For example, XL-139 can reduce the activity of HH signaling pathway, reduce cell proliferation, while induce apoptosis of esophageal cancer cells in vitro. 447 XL-139 can inhibit amyloblastoma cells with SMO-L412F mutation resistant to vismodegib. 448 XL-139 combined with gemcitabine can significantly inhibit the growth of CCC in the subcutaneous xenotransplantation model of mice. 276 Two clinical studies were designed to explore the effect of XL-139 combined with dasatinib in the treatment of leukemia, but the trial failed to proceed as expected ( NCT01218477 , NCT01357655 ). Therefore, further research is needed to reveal the safety and effectiveness of XL-139.

LEQ-506

LEQ-506 is a small molecule inhibitor of Smo, and there are few relevant studies at present. For D473H mutant cells resistant to vismodegib and sonidegib, LEQ-506 was not affected and showed inhibitory effect. 379 In addition, in vivo study has proved that LEQ-506 at 1% concentration can effectively inhibit the expression of Gli1 (80–90%) in the skin cells of depilated mice. 449

TAK-441

TAK-441 is an oral small molecule Smo inhibitor. Preclinical studies showed that its 50% inhibitory concentration (IC50) on Gli1 transcriptional activity was 4.4 nmol/L. 450 Similar to LEQ-506, TAK-441 can be used to treat D473H mutants resistant to vismodegib. 380 In vivo studies have proved that TAK-441 can inhibit Gli1 mRNA expression and tumor progression in castration resistant PCa and xenotransplantation of pancreatic tumor in mice. 451 , 452 A phase I clinical trial used TAK-441 to treat 34 patients with solid tumors, including colorectal cancer (26%), BCC (21%) and pancreatic cancer (9%). The results showed that TAK-441 was well tolerated and had preliminary anti-tumor activity. 453 The common adverse reactions of TAK-441 during treatment are taste disorder, fatigue, nausea and muscle spasm, mostly mild to moderate. 453

Itraconazole

Itraconazole is a drug to treat systemic fungal infection, especially in patients with low immune function and cancer. 454 In 2010, it was found that itraconazole could inhibit HH signaling pathway by preventing the accumulation of Smo in primary cilia. 455 The unique mechanism of action makes itraconazole a feasible choice for the treatment of other HH signaling pathway inhibitors resistance (such as vismodegib). Many in vivo and in vitro studies have proved that itraconazole can effectively suppress the proliferation of cancer cells, including MB, oral squamous cell carcinoma, gastric cancer, malignant pleural mesothelioma, etc. 455 – 458 Phase II clinical trial showed that after treatment with itraconazole in 19 patients with basal cells, cell proliferation decreased by 45% ( P = 0.04), HH signaling pathway activity decreased by 65% ( P = 0.03), and tumor area decreased by 24%. 459

MRT-92

MRT-92 is a small molecule inhibitor based on acyl guanidine or acyl thiourea scaffold, which can bind to the whole 7-transmembrane domain of Smo, and is insensitive to human D473H. 460 , 461 When inhibiting the proliferation of rat cerebellar granule cells by more than 50%, the required dose of MRT-92 was 0.3 μM and 3 μM for vismodegib. 461 Further studies showed that MRT-92 could inhibit the growth of melanoma cells in vitro and xenograft melanoma in mice by inducing DNA damage and G2/M cell cycle arrest. 462 Another study identified a new BRD4-SOX2 transcription complex, which is related to the non-standard activation of Gli1 in melanoma. 463 The researchers combined the powerful BRD4 degrading agent MZ1 with MRT-92, showing a synergistic anti-proliferation effect on melanoma cells. 463 These studies have demonstrated the potential of MRT-92 single drug therapy and multi-drug therapy for melanoma. More studies will help further reveal the safety and efficacy of MRT-92.

PF-5274857

PF-5274857 is an oral Smo antagonist. In vivo studies have shown that it can effectively penetrate the blood-brain barrier and inhibit the activity of Smo protein in the brain of mice with primary MB, thereby improving the survival rate of animals. 464 PF-5274857 has potential in the treatment of brain tumors driven by the activated HH signaling pathway or brain metastasis of primary tumors, but there is still a lack of further research.

Gli inhibitor

The nuclear transcription factor Gli is a downstream protein of HH signaling pathway, and inhibitors that target the Gli protein may block its binding to downstream genes and exert an inhibitory effect on HH signaling pathway. 465 Although Smo inhibitors have made good progress in the treatment of cancer, the drug-resistant mutations that they cause cannot be ignored. 466 Studies have shown that inhibitors targeting Gli proteins are effective against primary and secondary drug resistance induced by Smo inhibitors. 467 Currently, inhibitors targeting Gli include GANT compounds, ATO-like compounds, and Hedgehog pathway inhibitors (HPIs).

GANT58 and GANT61

The first inhibitors GANT58 and GANT61, which can inhibit Gli protein production, were identified by representative screening in HEK293 cells transiently expressing Gli1 and Gli-dependent luciferase reporter. 468 GANT58 and GANT61 have no effect on other cancer signaling pathways (e.g. TNF signaling/-NF-κB, glucocorticoid and MAPK pathways), and therefore they are highly selective for Gli. 468 GANTs can inhibit the proliferation of a variety of cancer cells. For example, GANT58 inhibited spheroid formation and invasion of cervical cancer stem cells undergoing EMT. 469 Moreover, it showed more potent cytotoxic effects in the face of cyclopamine-resistant T-ALL cells. 470

Compared to GANT58, GANT61 has a significant inhibitory effect on more types of cancer cells. For example, in vitro studies have shown that GANT61 can inhibit the proliferation and invasiveness of breast cancer, head and neck squamous cell carcinoma, HCC, ovarian plasmacytoma, and PCa. 471 – 475 Similar findings were found in in vivo studies, for example, Chang et al. found that the mean volume of cervical cancer in mice after 28 days of GANT61 treatment was significantly reduced compared to the control group (1467.39 ± 403.4 mm 3 Vs 460.73 ± 91.01 mm 3 ). 476 In addition, GANT61 also inhibited the growth of PCa, MB and rhabdomyosarcoma in vivo. 477 , 478 Currently, an increasing number of studies are using GANT61 as a positive control for identifying Gli-specific drugs. Notably, GANT61 under physiological conditions is unstable and rapidly hydrolyzes to aldehydes (GANT61-A) and diamine derivatives (GANT61-D). 479 GANT61-A lacked biological activity on HH signaling while GANT61-D could inhibit Gli transcription. 479 This nature limited the applicability of GANT61 and no clinical trials have been conducted so far.

ATO and darinaparsin (ZIO-101)

ATO is an arsenic compound that has been approved by the FDA as a first-line drug for the treatment of APL, with fewer metastases and longer survival after treatment. 480 ATO exerts its therapeutic effects by inducing promyelocytic leukemia-retinoic acid receptor multimerization, sumoylation and proteasomal degradation. 481 In 2010, ATO was validated as a Gli inhibitor, which inhibited Gli transcription and reduced target gene expression by acting directly on the zinc finger structural domain, thereby preventing Gli accumulation in primary cilia and affecting HH signaling pathway. 482 , 483 ATO, on the other hand, does not affect the interaction between Gli and DNA. 484 Yang et al. showed that after 28 months of single ATO treatment, 39 APL patients (86.67%) achieved complete hematological remission, and these patients showed significant downregulation of Gli2 and Smo gene expression. 485 In addition, several in vitro studies have shown that ATO can inhibit pancreatic cancer, osteosarcoma, rhabdomyosarcoma, malignant pleural mesothelioma and MB cells by acting on Gli. 458 , 484 , 486 – 488 ATO has been used as a first-line agent in the treatment of APL, but its clinical use in solid tumors is limited by a number of factors, including severe side effects, low drug solubility, and rapid renal clearance. 489 Pharmacology, drug combinations, and nano-drug delivery systems have all been effective in increasing the therapeutic potential of ATO. 490

The toxicity of ATO limits its clinical use in solid tumors, so researchers have developed new arsenic analogs to address this issue. Darinaparsin (S-dimethylarsino-glutathione, ZIO-101) is an organic small molecule arsenic compound, and like other arsenic compounds, the arsenic in darinaparsin can bind glutathione and act on the zinc finger structure of Gli protein. 491 Darinaparsin has better antitumor activity and less systemic toxicity than ATO, and intracellular arsenic levels increase faster, higher, and more consistently than ATO. 492 – 494 Furthermore, compared to ATO, darinaparsin showed significantly higher in vitro cytotoxicity and radiosensitizing activity against solid tumor cells under normoxia and hypoxia without affecting normal bone marrow. 495 Studies have shown that darinaparsin inhibits the proliferation of cancer cells and the growth of prostate tumors in mice by inhibiting Gli2 transcription. 496 Phase I clinical trials of darinaparsin for refractory solid tumors and phase II clinical trials of Hodgkin’s lymphoma have shown satisfied performance. 497 , 498 However, in vivo safety of darinaparsin still requires further study.

HPIs

HPI is a class of small molecules that directly antagonize Gli, independent of PI3K-AKT, PKA, MAPK and other related pathways. 499 Each HPI has a unique mechanism of action: (1) HPI-1 inhibits the activation of HH signaling pathway induced by Sufu deletion or Gli overexpression, suppresses Gli protein modification, and affects its function as a transcription factor/cofactor; (2) HPI-2 is less effective against exogenous Gli1 but may interfere with the conversion of full-length Gli2 into a transcriptional activator; (3) HPI-3 inhibits the formation of activated Gli2; (4) HPI-4 acts by disrupting ciliogenesis without affecting Gli2 formation. 499 In vitro studies have shown that HPI-1 can effectively inhibit the proliferation of small cell lung cancer, breast cancer and other tumor cells. 471 , 500 , 501 In addition, Wei et al. showed that HPI-4 treatment of chondrosarcoma cells significantly decreased the expression of ciliary microtubule transport protein Ift88, Gli protein, and Ptch1 protein, and impaired cell proliferation and invasion ability. 502 However, the low bioavailability of HPI in vivo due to its high lipophilicity and poor water solubility has limited further studies. 503

Other drugs may target HH signaling pathway

In addition to small molecule inhibitors, there are several inhibitors that can target HH signaling pathway, such as natural compounds and LncRNA. Natural compounds are easy to apply, highly available and acceptable therapeutic methods, usually targeting multiple signaling pathways. 504 It has been found that many natural compounds can target HH signaling pathway and inhibit the proliferation of cancer cells. 504 Among them, vitamin D3, also known as cholecalciferol, is the most studied and it is formed by 7-dehydrocholesterol after dehydrogenation of cholesterol by ultraviolet radiation. The A-ring of vitamin D3 can directly bind to Smo and inhibit HH signal transduction. 505 Studies have shown that vitamin D3 can reduce the expression of Gli1 and Ptch and cell proliferation in mouse BCC cell line, and this inhibition is carried out in an independent manner of vitamin D receptor. 506 At present, several clinical phase I and phase III trials of vitamin D3 are under way to study the role of vitamin D3 monotherapy or combination therapy in non-Hodgkin’s lymphoma and BCC ( NCT03078855 , NCT02553447 , NCT0343441). Since the function of these natural drugs targeting HH signaling pathway has not been fully revealed, we did not include the discussion of these drugs in the current review. Detailed information on natural medicines can be obtained from Table 4 . Table 4 Natural compounds and ncRNAs targeting HH signaling in cancers Name Features HH signaling target Cancer Model Effect Novel natural compounds Berberine 517 GI disease treatment Gli1, Ptch1 Primary intracranial MB In vitro and vivo Tumor growth reduction (37.5%) Cynanbungeigenin C/Cynanbungeigenin D 518 Health care drugs Gli MB In vitro and vivo Inhibition of cell viability and proliferation Thymoquinone 519 Anti-oxidant, anti-tumor Shh, Gli1 PCa In vitro and vivo Inhibition of cell viability and proliferation Resveratrol 520 , 521 Anti-aging, anti-tumor Gli1 GC In vitro Cancer cell invasion and metastasis inhibition Ptch, Smo PC In vitro Inhibition of cell viability and increase in apoptosis rate Curcumin 522 – 525 Food additives Gli1 Malignant glioma In vitro and vivo Tumor growth reduction (71.4%) Shh, Smo, Gli1, Gli2 Lung cancer In vitro Inhibition of cell proliferation and increase in apoptosis rate Shh, Smo, Gli PC In vitro Inhibition of cell EMT, proliferation and migration Shh, Gli1, Ptch1 MB In vitro Inhibition of cell viability and increase in apoptosis EGCG 401 , 526 – 528 Anti-oxidant, anti-tumor Gli1, Smo Tongue and liver cancer In vivo Limiting histological carcinogenesis Ptch1, Smo, Gli1 Liver cancer In vivo Limiting histological carcinogenesis Smo, Ptch1, Ptch2, Gli PC In vitro Inhibition of cell proliferation and increase in apoptosis Gli1, Ptch Chondrosarcoma In vitro Inhibition of cell proliferation and increase in apoptosis Ellagic acid 529 Anti-tumor Gli1, Gli2 PC In vivo Tumor growth and metastasis reduction (41.2%) Saikosaponin B1/Saikosaponin D 530 Anti-tumor Smo MB In vitro and vivo Inhibition of cell proliferation and tumor growth Genistein 531 , 532 Estrogen-like activity Smo, Gli1 BC In vivo Tumor growth reduction (68%) Gli1 PCa In vivo Tumor growth reduction (58.3%) Glabrescione B 533 Gli1, Ptch1 MB In vivo Tumor growth reduction (63.6%) Gli1, Ptch1 BCC In vitro Tumor growth reduction (71.4%) Silibinin 534 Hepatoprotective drugs Gli1, Gli2 RCC In vivo Tumor growth reduction (64.9%) Inoscavin A 535 Smo CC In vitro and vivo Inhibition of cell proliferation and tumor growth Acoschimperoside P, 2’-acetate 536 Gli1, Ptch1 PC In vitro Inhibition of cancer cell proliferation and migration Apigenin 537 Anti-cancer, anti-viral Gli1 PCa In vitro Inhibition of cancer cell proliferation and migration Baicalein 537 Treatment of paralysis after cerebrovascular disease Gli1 PCa In vitro Inhibition of cancer cell proliferation and migration Betulinic acid 538 Anti-cancer Gli1, Ptch1 PC and PCa In vitro Inhibition of cancer cell proliferation Deguelin 539 Insect poisoning, anti-cancer Gli1, Ptch1, Sufu PC In vitro Inhibition of cell migration and increased apoptosis Germacranolide 540 Gli1 PC In vitro Inhibition of cancer cell proliferation Physalin F & B 541 Anti-inflammatory, immunomodulatory Gli1, Gli2, Ptch1 PC In vitro Inhibition of cancer cell proliferation Sutherlandioside D 542 Anti-cancer Gli1, Ptch1 PCa In vitro Inhibition of cancer cell proliferation Sulforaphene 543 Anti-cancer Gli1 BC In vitro Cell invasion and metastasis inhibition Sulforaphane 544 Anti-oxidant, anti-tumor Smo, Gli1, Gli2 PC In vivo Tumor weight reduction (45.0%) Vitamin D3 252 , 506 Promote calcium and phosphorus absorption Gli2 RCC In vivo Tumor growth reduction (81.4%) Gli1 BCC In vitro and vivo Tumor growth reduction NcRNA LncRNA GAS5 545 Sufu TNBC In vivo Increased apoptosis in cancer cells LncRNA EGOT 546 Gli1, Smo, Ptch1, Hhip BC In vitro and vivo Inhibition of cell viability and migration capacity LncRNA LIFR-AS1 547 Sufu BC In vitro and vivo Inhibition of cancer cell proliferation and migration miR-7-5p 548 , 549 Smo GC In vitro Inhibition of cancer cell proliferation and migration Gli3 Bladder cancer In vitro and vivo Inhibition of cancer cell proliferation and migration miR-125b 550 Smo MB In vivo Inhibition of cancer cell proliferation and migration miR-141-3p 551 Gli2 Osteosarcoma In vitro and vivo Inhibition of cancer cell proliferation and increased apoptosis in cancer cells miR-182-5p 304 Gli1, Gli2 Lung cancer In vitro Cell proliferation inhibition and increased sensitivity to cisplatin miR-202 552 Gli2 Osteosarcoma In vitro and vivo Inhibition of cancer cell proliferation and increased apoptosis in cancer cells miR-218 553 , 554 Gli3 Cervical cancer In vitro and vivo Inhibition of cancer cell proliferation and migration Gli1 PCa In vitro Inhibition of cancer cell proliferation, metastasis and EMT miR-205HG 555 Ptch1 EC In vitro and vivo Tumor volume reduction (39.4%) miR-367-3p 556 Gli1, Gli2 PCa In vitro and vivo Inhibition of cancer cell proliferation and migration miR-361-3p 557 Gli1, Gli3 Retinoblastoma In vivo Inhibition of cancer cell proliferation and migration miR-324-3p 558 Gli3 NC In vitro and vivo Inhibition of cancer cell proliferation miR-324-5p 550 , 559 , 560 Smo, Gli1 MB In vivo Inhibition of cancer cell proliferation and migration Gli1 Glioma In vitro Inhibition of cancer cell survival Smo, Gli1 MM In vitro and vivo Inhibition of cancer cell proliferation and increased apoptosis in cancer cells miR-326 308 , 550 , 561 , 562 Smo MB In vivo Inhibition of cancer cell proliferation and migration Smo Glioblastoma In vitro and vivo Inhibition of cancer stem cell self-renewal and stemness Smo Osteosarcoma In vitro and vivo Inhibition of cancer cell proliferation and migration Smo CML In vitro and vivo Inhibition of cancer cell proliferation and increased apoptosis in cancer cells miR-338-3p 563 , 564 Smo CRC In vitro Inhibition of cancer cell proliferation and migration Smo Glioma In vitro Inhibition of cancer cell proliferation and migration miR-431 565 Gli Papillary thyroid carcinoma In vitro and vivo Inhibition of cancer cell proliferation and migration miR-506 566 Gli3 Cervical cancer In vitro and vivo Inhibition of cancer cell proliferation and increased apoptosis in cancer cells miR-584 567 Gli1 Cervical cancer In vitro and vivo Inhibition of cancer cell proliferation and migration miR-873 568 Gli1 Cervical cancer In vitro and vivo Inhibition of cancer cell proliferation, metastasis and EMT miR-873-5p 569 Gli1 GC In vitro Inhibition of cancer cell proliferation and migration miR-1271 570 Smo MM In vitro and vivo Inhibition of cancer cell proliferation and migration BCC Basal cell carcinoma, PCa prostate cancer, MB medulloblastoma, CRC colorectal cancer, TNBC triple negative breast cancer, PC pancreatic cancer, MM multiple myeloma, CML chronic myelomonocytic leukemia, EC esophageal cancer, BC breast cancer, CC colon cancer, GC gastric cancer, RCC renal cell carcinoma, NC nasopharyngeal carcinoma

Non-coding RNA (ncRNA) refers to RNA that does not encode proteins and operates at the RNA level. Recent studies have shown that ncRNA can regulate HH signaling pathway by changing Gli1/2, Smo and Ptch1, such as lncRNA, miRNA and circular RNA (circRNA). 507 LncRNA can regulate HH signaling pathway through activation or inhibition, which is related to tumor initiation or progression, chemotherapy resistance, recurrence and other processes. 508 The diagnosis or treatment methods based on lncRNA are promising. In Table 4 , we summarized ncRNAs that inhibit cancer development through HH signaling pathway. The existing challenge is how to deliver the specificity of oligonucleotide inhibitors to tumor targets. At present, nano based drug delivery systems are being developed to deliver oligonucleotide inhibitors, such as liposomes, exosomes, nanoparticles or viral vectors. 509 It is hoped that with the progress of research, more ncRNAs can be approved for clinical treatment.

Challenges of HH-targeted therapies

At present, the selective Smo inhibitors vismodegib and sonidegib have been approved by FDA for clinical treatment for cancers. However, the acquired drug resistance of cancer patients to vismodegib proves the clinical limitation of targeting Smo. Therefore, new inhibitors of HH signaling pathway have been developed to overcome this drug resistance, such as taladegib, LEQ-506 and TAK-441. Their effectiveness and safety need to be further validated in clinical trials. Furthermore, some natural compounds can affect HH signaling transduction through Smo, Gli1, Sufu and related factors. For example, vitamin D3 has entered clinical trials to evaluate its effect on non-Hodgkin’s lymphoma. Yet, these natural compounds have not been proved to be direct targets of HH signaling pathway. This can be further determined by using detailed in vivo and in vitro models. In addition, the bioavailability of many natural products is relatively low, and the concentrations used in in vitro studies cannot be achieved under physiological conditions. Therefore, it is necessary to determine the blood level at which natural products act. NcRNAs can mediate HH signaling pathway by changing Gli1/2, Smo and Ptch1 expression. Nanobased drug delivery systems are developed to deliver oligonucleotide inhibitors, such as liposomes, exosomes, nanoparticles and viral vectors. With the progress of these studies, it will be more conducive to targeted treatment of cancers with ncRNA. Finally, HH signaling transduction pathway also cooperates with other carcinogenic pathways, such as PI3K, MAPK, KRAS/BRAF and TGF-β, etc. It is beneficial to use HH signaling pathway inhibitors as combination or adjuvant therapy in cancer. Existing clinical trials have focused on the combination of HH signaling pathway inhibitors with targeted drugs of other pathways. As such, a future goal should be to define the specific function of drugs targeting HH signaling pathway, including their in vivo effectiveness, safety, side effects, etc. A deeper understanding of the mechanisms of HH-targeted therapies will prompt new treatments and continue to offer potential therapeutic targets for cancer.

Conclusion and future perspective

Early literature primarily focused on defining the function of HH signaling pathway in embryonic development. Recent studies have begun to reveal that the orchestration of HH signaling is critical for healthy cell function. Dysregulation of HH signaling pathway is associated with the development and progression of numerous cancers. Therefore, understanding the integrative nature of HH signaling pathway has opened up the potential for new therapeutic targets for cancer. A variety of drugs targeting HH signaling pathway have been developed, and some of which have been approved as for clinical treatment for cancer. Notably, most research of the inhibitors targeting HH signaling pathway are still in the early stages. The results of several clinical trials are unsatisfactory, owing to the fact that the efficacy and safety of the drugs are not well documented in preclinical studies. Meanwhile, certain drugs targeting HH signaling pathway show limited specificity, which is due to the lack of sufficient studies to verify the mechanism of the specific action on HH signaling pathway. As implied above, with new therapeutic targets being identified at a rapid rate, a more comprehensive understanding of the mechanisms of HH-targeted therapy will solve the existing problems in the application of these drugs and pave the way for a new clinical paradigm.

In summary, our review comprehensively summarizes the function of HH signaling pathway in tissue homeostasis and cancer development. Importantly, we discussed the current application, advantages and challenges of HH signaling pathway targeted therapies, providing valuable insight and important implications for the exciting translational innovations in the future.

These authors contributed equally: Junjun Jing, Zhuoxuan Wu, Jiahe Wang

Acknowledgements

This work was supported by NSFC grants 82222015, 82171001 and 81800928, Young Elite Scientist Sponsorship Program by CAST No. 2020QNRC001, Research Funding from West China School/Hospital of Stomatology Sichuan University RCDWJS2023-(1).

Author contributions

J.J., Z.W. and J.W. contributed equally to this work. J.J., Z.W., J.W., G.L., H.L. performed literature searching and summary. J.J., Z.W. and J.W. wrote the manuscript; and Y.F. and C.Z. provided valuable discussion and revised the manuscript. All authors have read and approved the article.

Competing interests

The authors declare no competing interests. C.Z., who is a member of the editorial board of Signal Transduction and Targeted Therapy, was not involved in the handling process of this manuscript.

References

1. Cavodeassi F Creuzet S Etchevers H The hedgehog pathway and ocular developmental anomalies Hum. Genet. 2019 138 917 936 30073412 10.1007/s00439-018-1918-8 PMC6710239 Cavodeassi, F., Creuzet, S. & Etchevers, H. The hedgehog pathway and ocular developmental anomalies. Hum. Genet. 138 , 917–936 (2019). 30073412 10.1007/s00439-018-1918-8 PMC6710239

2. Ingham P Drosophila segment polarity mutants and the rediscovery of the hedgehog pathway genes Curr. Top. Dev. Biol. 2016 116 477 488 26970635 10.1016/bs.ctdb.2016.01.007 Ingham, P. Drosophila segment polarity mutants and the rediscovery of the hedgehog pathway genes. Curr. Top. Dev. Biol. 116 , 477–488 (2016). 26970635 10.1016/bs.ctdb.2016.01.007

3. Ingham P Hedgehog signaling Curr. Top. Dev. Biol. 2022 149 1 58 35606054 10.1016/bs.ctdb.2022.04.003 Ingham, P. Hedgehog signaling. Curr. Top. Dev. Biol. 149 , 1–58 (2022). 35606054 10.1016/bs.ctdb.2022.04.003

4. Gonzalez D Medici D Signaling mechanisms of the epithelial-mesenchymal transition Sci. Signal 2014 7 re8 25249658 10.1126/scisignal.2005189 PMC4372086 Gonzalez, D. & Medici, D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal 7 , re8 (2014). 25249658 10.1126/scisignal.2005189 PMC4372086

5. Briscoe J Thérond P The mechanisms of Hedgehog signalling and its roles in development and disease Nat. Rev. Mol. Cell Biol. 2013 14 416 429 23719536 10.1038/nrm3598 Briscoe, J. & Thérond, P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14 , 416–429 (2013). 23719536 10.1038/nrm3598

6. Jiang J Hedgehog signaling mechanism and role in cancer Semin Cancer Biol. 2022 85 107 122 33836254 10.1016/j.semcancer.2021.04.003 PMC8492792 Jiang, J. Hedgehog signaling mechanism and role in cancer. Semin Cancer Biol. 85 , 107–122 (2022). 33836254 10.1016/j.semcancer.2021.04.003 PMC8492792

7. Katoh M Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers Clin. Sci. (Lond.) 2019 133 953 970 31036756 10.1042/CS20180845 Katoh, M. Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers. Clin. Sci. (Lond.) 133 , 953–970 (2019). 31036756 10.1042/CS20180845

8. Chen X Processing and turnover of the Hedgehog protein in the endoplasmic reticulum J. Cell Biol. 2011 192 825 838 21357747 10.1083/jcb.201008090 PMC3051819 Chen, X. et al. Processing and turnover of the Hedgehog protein in the endoplasmic reticulum. J. Cell Biol. 192 , 825–838 (2011). 21357747 10.1083/jcb.201008090 PMC3051819

9. Lum L Beachy PA The Hedgehog response network: sensors, switches, and routers Science 2004 304 1755 1759 15205520 10.1126/science.1098020 Lum, L. & Beachy, P. A. The Hedgehog response network: sensors, switches, and routers. Science 304 , 1755–1759 (2004). 15205520 10.1126/science.1098020

10. Rohatgi R Scott MP Patching the gaps in Hedgehog signalling Nat. Cell Biol. 2007 9 1005 1009 17762891 10.1038/ncb435 Rohatgi, R. & Scott, M. P. Patching the gaps in Hedgehog signalling. Nat. Cell Biol. 9 , 1005–1009 (2007). 17762891 10.1038/ncb435

11. Hui C Angers S Gli proteins in development and disease Annu Rev. Cell Dev. Biol. 2011 27 513 537 21801010 10.1146/annurev-cellbio-092910-154048 Hui, C. & Angers, S. Gli proteins in development and disease. Annu Rev. Cell Dev. Biol. 27 , 513–537 (2011). 21801010 10.1146/annurev-cellbio-092910-154048

12. Svärd J Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway Dev. Cell 2006 10 187 197 16459298 10.1016/j.devcel.2005.12.013 Svärd, J. et al. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev. Cell 10 , 187–197 (2006). 16459298 10.1016/j.devcel.2005.12.013

13. Goetz S Anderson K The primary cilium: a signalling centre during vertebrate development Nat. Rev. Genet. 2010 11 331 344 20395968 10.1038/nrg2774 PMC3121168 Goetz, S. & Anderson, K. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11 , 331–344 (2010). 20395968 10.1038/nrg2774 PMC3121168

14. May S Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli Dev. Biol. 2005 287 378 389 16229832 10.1016/j.ydbio.2005.08.050 May, S. et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev. Biol. 287 , 378–389 (2005). 16229832 10.1016/j.ydbio.2005.08.050

15. Bangs F Anderson K Primary cilia and mammalian hedgehog signaling Cold Spring Harb. Perspect. Biol. 2017 9 a028175 27881449 10.1101/cshperspect.a028175 PMC5411695 Bangs, F. & Anderson, K. Primary cilia and mammalian hedgehog signaling. Cold Spring Harb. Perspect. Biol. 9 , a028175 (2017). 27881449 10.1101/cshperspect.a028175 PMC5411695

16. Hooper J Scott M Communicating with hedgehogs Nat. Rev. Mol. Cell Biol. 2005 6 306 317 15803137 10.1038/nrm1622 Hooper, J. & Scott, M. Communicating with hedgehogs. Nat. Rev. Mol. Cell Biol. 6 , 306–317 (2005). 15803137 10.1038/nrm1622

17. Lewis P Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1 Cell 2001 105 599 612 11389830 10.1016/s0092-8674(01)00369-5 Lewis, P. et al. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105 , 599–612 (2001). 11389830 10.1016/s0092-8674(01)00369-5

18. St-Jacques B Hammerschmidt M McMahon A Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation Genes Dev. 1999 13 2072 2086 10465785 10.1101/gad.13.16.2072 PMC316949 St-Jacques, B., Hammerschmidt, M. & McMahon, A. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13 , 2072–2086 (1999). 10465785 10.1101/gad.13.16.2072 PMC316949

19. Baldinotti F Novel familial variant of the desert hedgehog gene: clinical findings in two sisters with 46,XY gonadal dysgenesis or 46,XX karyotype and literature review Horm. Res. Paediatr. 2018 89 141 149 29471294 10.1159/000485507 Baldinotti, F. et al. Novel familial variant of the desert hedgehog gene: clinical findings in two sisters with 46,XY gonadal dysgenesis or 46,XX karyotype and literature review. Horm. Res. Paediatr. 89 , 141–149 (2018). 29471294 10.1159/000485507

20. Kong J Siebold C Rohatgi R Biochemical mechanisms of vertebrate hedgehog signaling Development 2019 146 dev166892 31092502 10.1242/dev.166892 PMC6550017 Kong, J., Siebold, C. & Rohatgi, R. Biochemical mechanisms of vertebrate hedgehog signaling. Development 146 , dev166892 (2019). 31092502 10.1242/dev.166892 PMC6550017

21. Riddle R Johnson R Laufer E Tabin C Sonic hedgehog mediates the polarizing activity of the ZPA Cell 1993 75 1401 1416 8269518 10.1016/0092-8674(93)90626-2 Riddle, R., Johnson, R., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75 , 1401–1416 (1993). 8269518 10.1016/0092-8674(93)90626-2

22. Bourikas D Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord Nat. Neurosci. 2005 8 297 304 15746914 10.1038/nn1396 Bourikas, D. et al. Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord. Nat. Neurosci. 8 , 297–304 (2005). 15746914 10.1038/nn1396

23. Hill S Fu M Garcia A Sonic hedgehog signaling in astrocytes Cell Mol. Life Sci. 2021 78 1393 1403 33079226 10.1007/s00018-020-03668-8 PMC7904711 Hill, S., Fu, M. & Garcia, A. Sonic hedgehog signaling in astrocytes. Cell Mol. Life Sci. 78 , 1393–1403 (2021). 33079226 10.1007/s00018-020-03668-8 PMC7904711

24. Ishii M Sun J Ting M Maxson R The development of the calvarial bones and sutures and the pathophysiology of craniosynostosis Curr. Top. Dev. Biol. 2015 115 131 156 26589924 10.1016/bs.ctdb.2015.07.004 Ishii, M., Sun, J., Ting, M. & Maxson, R. The development of the calvarial bones and sutures and the pathophysiology of craniosynostosis. Curr. Top. Dev. Biol. 115 , 131–156 (2015). 26589924 10.1016/bs.ctdb.2015.07.004

25. King P Paul A Laufer E Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages Proc. Natl Acad. Sci. USA 2009 106 21185 21190 19955443 10.1073/pnas.0909471106 PMC2786892 King, P., Paul, A. & Laufer, E. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc. Natl Acad. Sci. USA 106 , 21185–21190 (2009). 19955443 10.1073/pnas.0909471106 PMC2786892

26. Rishikaysh P Signaling involved in hair follicle morphogenesis and development Int J. Mol. Sci. 2014 15 1647 1670 24451143 10.3390/ijms15011647 PMC3907891 Rishikaysh, P. et al. Signaling involved in hair follicle morphogenesis and development. Int J. Mol. Sci. 15 , 1647–1670 (2014). 24451143 10.3390/ijms15011647 PMC3907891

27. Hosoya A Sonic hedgehog signaling and tooth development Int J. Mol. Sci. 2020 21 1587 32111038 10.3390/ijms21051587 PMC7084732 Hosoya, A. et al. Sonic hedgehog signaling and tooth development. Int J. Mol. Sci. 21 , 1587 (2020). 32111038 10.3390/ijms21051587 PMC7084732

28. Varjosalo M Taipale J Hedgehog signaling J. Cell Sci. 2007 120 3 6 17182898 10.1242/jcs.03309 Varjosalo, M. & Taipale, J. Hedgehog signaling. J. Cell Sci. 120 , 3–6 (2007). 17182898 10.1242/jcs.03309

29. Qi X Li X Mechanistic insights into the generation and transduction of hedgehog signaling Trends Biochem. Sci. 2020 45 397 410 32311334 10.1016/j.tibs.2020.01.006 PMC7174405 Qi, X. & Li, X. Mechanistic insights into the generation and transduction of hedgehog signaling. Trends Biochem. Sci. 45 , 397–410 (2020). 32311334 10.1016/j.tibs.2020.01.006 PMC7174405

30. Pepinsky R Identification of a palmitic acid-modified form of human Sonic hedgehog J. Biol. Chem. 1998 273 14037 14045 9593755 10.1074/jbc.273.22.14037 Pepinsky, R. et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J. Biol. Chem. 273 , 14037–14045 (1998). 9593755 10.1074/jbc.273.22.14037

31. Buglino J Resh M Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog J. Biol. Chem. 2008 283 22076 22088 18534984 10.1074/jbc.M803901200 PMC2494920 Buglino, J. & Resh, M. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J. Biol. Chem. 283 , 22076–22088 (2008). 18534984 10.1074/jbc.M803901200 PMC2494920

32. Chamoun Z Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal Science 2001 293 2080 2084 11486055 10.1126/science.1064437 Chamoun, Z. et al. Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293 , 2080–2084 (2001). 11486055 10.1126/science.1064437

33. Tukachinsky H Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand Cell Rep. 2012 2 308 320 22902404 10.1016/j.celrep.2012.07.010 PMC3682496 Tukachinsky, H. et al. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand. Cell Rep. 2 , 308–320 (2012). 22902404 10.1016/j.celrep.2012.07.010 PMC3682496

34. Ehring K Grobe K Dispatching plasma membrane cholesterol and Sonic Hedgehog dispatch: two sides of the same coin? Biochem. Soc. Trans. 2021 49 2455 2463 34515747 10.1042/BST20210918 PMC8589413 Ehring, K. & Grobe, K. Dispatching plasma membrane cholesterol and Sonic Hedgehog dispatch: two sides of the same coin? Biochem. Soc. Trans. 49 , 2455–2463 (2021). 34515747 10.1042/BST20210918 PMC8589413

35. Ohlig S Sonic hedgehog shedding results in functional activation of the solubilized protein Dev. Cell 2011 20 764 774 21664575 10.1016/j.devcel.2011.05.010 Ohlig, S. et al. Sonic hedgehog shedding results in functional activation of the solubilized protein. Dev. Cell 20 , 764–774 (2011). 21664575 10.1016/j.devcel.2011.05.010

36. Zeng X A freely diffusible form of Sonic hedgehog mediates long-range signalling Nature 2001 411 716 720 11395778 10.1038/35079648 Zeng, X. et al. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411 , 716–720 (2001). 11395778 10.1038/35079648

37. Ramsbottom S Pownall M Regulation of Hedgehog signalling inside and outside the cell J. Dev. Biol. 2016 4 23 27547735 10.3390/jdb4030023 PMC4990124 Ramsbottom, S. & Pownall, M. Regulation of Hedgehog signalling inside and outside the cell. J. Dev. Biol. 4 , 23 (2016). 27547735 10.3390/jdb4030023 PMC4990124

38. Takei Y Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans Development 2004 131 73 82 14645127 10.1242/dev.00913 Takei, Y. et al. Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans. Development 131 , 73–82 (2004). 14645127 10.1242/dev.00913

39. The I Bellaiche Y Perrimon N Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan Mol. Cell 1999 4 633 639 10549295 10.1016/s1097-2765(00)80214-2 The, I., Bellaiche, Y. & Perrimon, N. Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. Mol. Cell 4 , 633–639 (1999). 10549295 10.1016/s1097-2765(00)80214-2

40. Chen Y Struhl G Dual roles for patched in sequestering and transducing Hedgehog Cell 1996 87 553 563 8898207 10.1016/s0092-8674(00)81374-4 Chen, Y. & Struhl, G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 87 , 553–563 (1996). 8898207 10.1016/s0092-8674(00)81374-4

41. La Sala G Modulation of Dhh signaling and altered Sertoli cell function in mice lacking the GPR37-prosaposin receptor FASEB J. 2015 29 2059 2069 25609427 10.1096/fj.14-269209 La Sala, G. et al. Modulation of Dhh signaling and altered Sertoli cell function in mice lacking the GPR37-prosaposin receptor. FASEB J. 29 , 2059–2069 (2015). 25609427 10.1096/fj.14-269209

42. Zhao C Desert hedgehog mediates the proliferation of medaka spermatogonia through smoothened signaling Reproduction 2022 163 209 218 35119381 10.1530/REP-21-0468 Zhao, C. et al. Desert hedgehog mediates the proliferation of medaka spermatogonia through smoothened signaling. Reproduction 163 , 209–218 (2022). 35119381 10.1530/REP-21-0468

43. Clark A Garland K Russell L Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules Biol. Reprod. 2000 63 1825 1838 11090455 10.1095/biolreprod63.6.1825 Clark, A., Garland, K. & Russell, L. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Biol. Reprod. 63 , 1825–1838 (2000). 11090455 10.1095/biolreprod63.6.1825

44. Sugito H Ihh signaling regulates mandibular symphysis development and growth J. Dent. Res. 2011 90 625 631 21297010 10.1177/0022034510397836 Sugito, H. et al. Ihh signaling regulates mandibular symphysis development and growth. J. Dent. Res. 90 , 625–631 (2011). 21297010 10.1177/0022034510397836

45. Ohba S Hedgehog signaling in skeletal development: roles of Indian Hedgehog and the mode of its action Int. J. Mol. Sci. 2020 21 6665 32933018 10.3390/ijms21186665 PMC7555016 Ohba, S. Hedgehog signaling in skeletal development: roles of Indian Hedgehog and the mode of its action. Int. J. Mol. Sci. 21 , 6665 (2020). 32933018 10.3390/ijms21186665 PMC7555016

46. King PJ Guasti L Laufer E Hedgehog signalling in endocrine development and disease J. Endocrinol. 2008 198 439 450 18524957 10.1677/JOE-08-0161 King, P. J., Guasti, L. & Laufer, E. Hedgehog signalling in endocrine development and disease. J. Endocrinol. 198 , 439–450 (2008). 18524957 10.1677/JOE-08-0161

47. Bonn-Breach R Structure of Sonic Hedgehog protein in complex with zinc(II) and magnesium(II) reveals ion-coordination plasticity relevant to peptide drug design Acta Crystallogr D. Struct. Biol. 2019 75 969 979 31692471 10.1107/S2059798319012890 PMC6834079 Bonn-Breach, R. et al. Structure of Sonic Hedgehog protein in complex with zinc(II) and magnesium(II) reveals ion-coordination plasticity relevant to peptide drug design. Acta Crystallogr D. Struct. Biol. 75 , 969–979 (2019). 31692471 10.1107/S2059798319012890 PMC6834079

48. Pathi S Comparative biological responses to human Sonic, Indian, and Desert hedgehog Mech. Dev. 2001 106 107 117 11472839 10.1016/s0925-4773(01)00427-0 Pathi, S. et al. Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech. Dev. 106 , 107–117 (2001). 11472839 10.1016/s0925-4773(01)00427-0

49. Hollier P Full-length Dhh and N-terminal Shh act as competitive antagonists to regulate angiogenesis and vascular permeability Cardiovasc Res. 2021 117 2489 2501 33063110 10.1093/cvr/cvaa285 Hollier, P. et al. Full-length Dhh and N-terminal Shh act as competitive antagonists to regulate angiogenesis and vascular permeability. Cardiovasc Res. 117 , 2489–2501 (2021). 33063110 10.1093/cvr/cvaa285

50. Carpenter D Characterization of two patched receptors for the vertebrate hedgehog protein family Proc. Natl Acad. Sci. USA 1998 95 13630 13634 9811851 10.1073/pnas.95.23.13630 PMC24870 Carpenter, D. et al. Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc. Natl Acad. Sci. USA 95 , 13630–13634 (1998). 9811851 10.1073/pnas.95.23.13630 PMC24870

51. Gong X Structural basis for the recognition of Sonic Hedgehog by human Patched1 Science 2018 361 eaas8935 29954986 10.1126/science.aas8935 Gong, X. et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 361 , eaas8935 (2018). 29954986 10.1126/science.aas8935

52. Ingham P Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein Curr. Biol. 2000 10 1315 1318 11069117 10.1016/s0960-9822(00)00755-7 Ingham, P. et al. Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein. Curr. Biol. 10 , 1315–1318 (2000). 11069117 10.1016/s0960-9822(00)00755-7

53. Qi X Schmiege P Coutavas E Li X Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex Science 2018 362 eaas8843 30139912 10.1126/science.aas8843 PMC6341491 Qi, X., Schmiege, P., Coutavas, E. & Li, X. Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex. Science 362 , eaas8843 (2018). 30139912 10.1126/science.aas8843 PMC6341491

54. Alfaro A Ptch2 mediates the Shh response in Ptch1−/− cells Development 2014 141 3331 3339 25085974 10.1242/dev.110056 PMC4199129 Alfaro, A. et al. Ptch2 mediates the Shh response in Ptch1−/− cells. Development 141 , 3331–3339 (2014). 25085974 10.1242/dev.110056 PMC4199129

55. Rahnama F Toftgård R Zaphiropoulos P Distinct roles of PTCH2 splice variants in Hedgehog signalling Biochem. J. 2004 378 325 334 14613484 10.1042/BJ20031200 PMC1223965 Rahnama, F., Toftgård, R. & Zaphiropoulos, P. Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem. J. 378 , 325–334 (2004). 14613484 10.1042/BJ20031200 PMC1223965

56. Byrne E Luchetti G Rohatgi R Siebold C Multiple ligand binding sites regulate the Hedgehog signal transducer smoothened in vertebrates Curr. Opin. Cell Biol. 2018 51 81 88 29268141 10.1016/j.ceb.2017.10.004 PMC5949240 Byrne, E., Luchetti, G., Rohatgi, R. & Siebold, C. Multiple ligand binding sites regulate the Hedgehog signal transducer smoothened in vertebrates. Curr. Opin. Cell Biol. 51 , 81–88 (2018). 29268141 10.1016/j.ceb.2017.10.004 PMC5949240

57. Kumari S Mitra A Bulusu G Structural dynamics of Smoothened (SMO) in the ciliary membrane and its interaction with membrane lipids Biochim. Biophys. Acta Biomembr. 2022 1864 183946 35483421 10.1016/j.bbamem.2022.183946 Kumari, S., Mitra, A. & Bulusu, G. Structural dynamics of Smoothened (SMO) in the ciliary membrane and its interaction with membrane lipids. Biochim. Biophys. Acta Biomembr. 1864 , 183946 (2022). 35483421 10.1016/j.bbamem.2022.183946

58. Wang C Structure of the human smoothened receptor bound to an antitumour agent Nature 2013 497 338 343 23636324 10.1038/nature12167 PMC3657389 Wang, C. et al. Structure of the human smoothened receptor bound to an antitumour agent. Nature 497 , 338–343 (2013). 23636324 10.1038/nature12167 PMC3657389

59. Zhao Y Tong C Jiang J Hedgehog regulates smoothened activity by inducing a conformational switch Nature 2007 450 252 258 17960137 10.1038/nature06225 Zhao, Y., Tong, C. & Jiang, J. Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450 , 252–258 (2007). 17960137 10.1038/nature06225

60. Chen Y Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened PLoS Biol. 2011 9 e1001083 21695114 10.1371/journal.pbio.1001083 PMC3114773 Chen, Y. et al. Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol. 9 , e1001083 (2011). 21695114 10.1371/journal.pbio.1001083 PMC3114773

61. Jia J Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I Nature 2004 432 1045 1050 15616566 10.1038/nature03179 Jia, J. et al. Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432 , 1045–1050 (2004). 15616566 10.1038/nature03179

62. Frank-Kamenetsky M Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists J. Biol. 2002 1 10 12437772 10.1186/1475-4924-1-10 PMC137065 Frank-Kamenetsky, M. et al. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J. Biol. 1 , 10 (2002). 12437772 10.1186/1475-4924-1-10 PMC137065

63. Sharpe H Wang W Hannoush R de Sauvage F Regulation of the oncoprotein smoothened by small molecules Nat. Chem. Biol. 2015 11 246 255 25785427 10.1038/nchembio.1776 Sharpe, H., Wang, W., Hannoush, R. & de Sauvage, F. Regulation of the oncoprotein smoothened by small molecules. Nat. Chem. Biol. 11 , 246–255 (2015). 25785427 10.1038/nchembio.1776

64. Kaushal J Batra S Rachagani S Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review Cell Mol. Life Sci. 2022 79 266 35486193 10.1007/s00018-022-04233-1 PMC9990174 Kaushal, J., Batra, S. & Rachagani, S. Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review. Cell Mol. Life Sci. 79 , 266 (2022). 35486193 10.1007/s00018-022-04233-1 PMC9990174

65. Lacour J Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms Br. J. Dermatol. 2002 Suppl 61 17 19 10.1046/j.1365-2133.146.s61.5.x 11966727 Lacour, J. Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. Br. J. Dermatol. Suppl 61 , 17–19 (2002). 10.1046/j.1365-2133.146.s61.5.x 11966727

66. Kim J The role of ciliary trafficking in Hedgehog receptor signaling Sci. Signal 2015 8 ra55 26038600 10.1126/scisignal.aaa5622 PMC4863716 Kim, J. et al. The role of ciliary trafficking in Hedgehog receptor signaling. Sci. Signal 8 , ra55 (2015). 26038600 10.1126/scisignal.aaa5622 PMC4863716

67. Chen Y Jiang J Decoding the phosphorylation code in Hedgehog signal transduction Cell Res. 2013 23 186 200 23337587 10.1038/cr.2013.10 PMC3567827 Chen, Y. & Jiang, J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res. 23 , 186–200 (2013). 23337587 10.1038/cr.2013.10 PMC3567827

68. Hu A Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate Cell Res. 2022 32 288 301 35121857 10.1038/s41422-022-00622-0 PMC8888579 Hu, A. et al. Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate. Cell Res. 32 , 288–301 (2022). 35121857 10.1038/s41422-022-00622-0 PMC8888579

69. Kong Z The cation-π interaction in cysteine-rich domain of smoothened is critical for its cholesterylation and function Acta Biochim. Biophys. Sin. (Shanghai) 2022 54 1171 1179 35904215 10.3724/abbs.2022090 PMC9828284 Kong, Z. et al. The cation-π interaction in cysteine-rich domain of smoothened is critical for its cholesterylation and function. Acta Biochim. Biophys. Sin. (Shanghai) 54 , 1171–1179 (2022). 35904215 10.3724/abbs.2022090 PMC9828284

70. Kim Y Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration Nat. Commun. 2020 11 1994 32332736 10.1038/s41467-020-15897-3 PMC7181751 Kim, Y. et al. Ptch2/Gas1 and Ptch1/Boc differentially regulate Hedgehog signalling in murine primordial germ cell migration. Nat. Commun. 11 , 1994 (2020). 32332736 10.1038/s41467-020-15897-3 PMC7181751

71. Echevarría-Andino M Allen B The hedgehog co-receptor BOC differentially regulates SHH signaling during craniofacial development Development 2020 147 dev189076 33060130 10.1242/dev.189076 PMC7758635 Echevarría-Andino, M. & Allen, B. The hedgehog co-receptor BOC differentially regulates SHH signaling during craniofacial development. Development 147 , dev189076 (2020). 33060130 10.1242/dev.189076 PMC7758635

72. Witt R Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation J. Biol. Chem. 2013 288 26275 26288 23867465 10.1074/jbc.M112.438937 PMC3764831 Witt, R. et al. Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation. J. Biol. Chem. 288 , 26275–26288 (2013). 23867465 10.1074/jbc.M112.438937 PMC3764831

73. Niewiadomski P Gli proteins: regulation in development and cancer Cells 2019 8 147 30754706 10.3390/cells8020147 PMC6406693 Niewiadomski, P. et al. Gli proteins: regulation in development and cancer. Cells 8 , 147 (2019). 30754706 10.3390/cells8020147 PMC6406693

74. Kasper M Regl G Frischauf A Aberger F GLI transcription factors: mediators of oncogenic Hedgehog signalling Eur. J. Cancer 2006 42 437 445 16406505 10.1016/j.ejca.2005.08.039 Kasper, M., Regl, G., Frischauf, A. & Aberger, F. GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur. J. Cancer 42 , 437–445 (2006). 16406505 10.1016/j.ejca.2005.08.039

75. Lichti-Kaiser K Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease Vitam. Horm. 2012 88 141 171 22391303 10.1016/B978-0-12-394622-5.00007-9 PMC3799816 Lichti-Kaiser, K. et al. Gli-similar proteins: their mechanisms of action, physiological functions, and roles in disease. Vitam. Horm. 88 , 141–171 (2012). 22391303 10.1016/B978-0-12-394622-5.00007-9 PMC3799816

76. Ma T Geniposide alleviates inflammation by suppressing MeCP2 in mice with carbon tetrachloride-induced acute liver injury and LPS-treated THP-1 cells Int. Immunopharmacol. 2015 29 739 747 26371859 10.1016/j.intimp.2015.08.045 Ma, T. et al. Geniposide alleviates inflammation by suppressing MeCP2 in mice with carbon tetrachloride-induced acute liver injury and LPS-treated THP-1 cells. Int. Immunopharmacol. 29 , 739–747 (2015). 26371859 10.1016/j.intimp.2015.08.045

77. Pearson R Krüppel-like transcription factors: a functional family Int. J. Biochem. Cell Biol. 2008 40 1996 2001 17904406 10.1016/j.biocel.2007.07.018 Pearson, R. et al. Krüppel-like transcription factors: a functional family. Int. J. Biochem. Cell Biol. 40 , 1996–2001 (2008). 17904406 10.1016/j.biocel.2007.07.018

78. Liao H Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of suppressor of fused Cell Death Dis. 2020 11 686 32826873 10.1038/s41419-020-02843-w PMC7442787 Liao, H. et al. Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of suppressor of fused. Cell Death Dis. 11 , 686 (2020). 32826873 10.1038/s41419-020-02843-w PMC7442787

79. Maloverjan A Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway J. Biol. Chem. 2010 285 30079 30090 20643644 10.1074/jbc.M110.133991 PMC2943318 Maloverjan, A. et al. Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway. J. Biol. Chem. 285 , 30079–30090 (2010). 20643644 10.1074/jbc.M110.133991 PMC2943318

80. Chen Y Dual phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium J. Biol. Chem. 2011 286 13502 13511 21317289 10.1074/jbc.M110.217604 PMC3075696 Chen, Y. et al. Dual phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. J. Biol. Chem. 286 , 13502–13511 (2011). 21317289 10.1074/jbc.M110.217604 PMC3075696

81. Pearse R Collier L Scott M Tabin C Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators Dev. Biol. 1999 212 323 336 10433824 10.1006/dbio.1999.9335 PMC4530617 Pearse, R., Collier, L., Scott, M. & Tabin, C. Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Dev. Biol. 212 , 323–336 (1999). 10433824 10.1006/dbio.1999.9335 PMC4530617

82. Zhang Y Structural insight into the mutual recognition and regulation between suppressor of fused and Gli/Ci Nat. Commun. 2013 4 2608 24217340 10.1038/ncomms3608 PMC5842692 Zhang, Y. et al. Structural insight into the mutual recognition and regulation between suppressor of fused and Gli/Ci. Nat. Commun. 4 , 2608 (2013). 24217340 10.1038/ncomms3608 PMC5842692

83. Zhou M Dose-dependent phosphorylation and activation of Hh pathway transcription factors Life Sci. Alliance 2022 5 e202201570 36271509 10.26508/lsa.202201570 PMC9445324 Zhou, M. et al. Dose-dependent phosphorylation and activation of Hh pathway transcription factors. Life Sci. Alliance 5 , e202201570 (2022). 36271509 10.26508/lsa.202201570 PMC9445324

84. Bonifas J Activation of expression of hedgehog target genes in basal cell carcinomas J. Invest. Dermatol. 2001 116 739 742 11348463 10.1046/j.1523-1747.2001.01315.x Bonifas, J. et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J. Invest. Dermatol. 116 , 739–742 (2001). 11348463 10.1046/j.1523-1747.2001.01315.x

85. Yang D BMI1 in the heart: novel functions beyond tumorigenesis EBioMedicine 2021 63 103193 33421944 10.1016/j.ebiom.2020.103193 PMC7804972 Yang, D. et al. BMI1 in the heart: novel functions beyond tumorigenesis. EBioMedicine 63 , 103193 (2021). 33421944 10.1016/j.ebiom.2020.103193 PMC7804972

86. Thompson E The many roles of c-Myc in apoptosis Annu Rev. Physiol. 1998 60 575 600 9558477 10.1146/annurev.physiol.60.1.575 Thompson, E. The many roles of c-Myc in apoptosis. Annu Rev. Physiol. 60 , 575–600 (1998). 9558477 10.1146/annurev.physiol.60.1.575

87. Duman-Scheel M Weng L Xin S Du W Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E Nature 2002 417 299 304 12015606 10.1038/417299a Duman-Scheel, M., Weng, L., Xin, S. & Du, W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417 , 299–304 (2002). 12015606 10.1038/417299a

88. Chuang P McMahon A Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein Nature 1999 397 617 621 10050855 10.1038/17611 Chuang, P. & McMahon, A. Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397 , 617–621 (1999). 10050855 10.1038/17611

89. Bouldin C Harfe B Aberrant FGF signaling, independent of ectopic hedgehog signaling, initiates preaxial polydactyly in Dorking chickens Dev. Biol. 2009 334 133 141 19616534 10.1016/j.ydbio.2009.07.009 Bouldin, C. & Harfe, B. Aberrant FGF signaling, independent of ectopic hedgehog signaling, initiates preaxial polydactyly in Dorking chickens. Dev. Biol. 334 , 133–141 (2009). 19616534 10.1016/j.ydbio.2009.07.009

90. Sasai N Toriyama M Kondo T Hedgehog signal and genetic disorders Front. Genet. 2019 10 1103 31781166 10.3389/fgene.2019.01103 PMC6856222 Sasai, N., Toriyama, M. & Kondo, T. Hedgehog signal and genetic disorders. Front. Genet. 10 , 1103 (2019). 31781166 10.3389/fgene.2019.01103 PMC6856222

91. Katoh Y Katoh M Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation Curr. Mol. Med. 2009 9 873 886 19860666 10.2174/156652409789105570 Katoh, Y. & Katoh, M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr. Mol. Med. 9 , 873–886 (2009). 19860666 10.2174/156652409789105570

92. Bigelow RL Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1 J. Biol. Chem. 2004 279 1197 1205 14555646 10.1074/jbc.M310589200 Bigelow, R. L. et al. Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J. Biol. Chem. 279 , 1197–1205 (2004). 14555646 10.1074/jbc.M310589200

93. Oliver TG Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors Proc. Natl Acad. Sci. USA 2003 100 7331 7336 12777630 10.1073/pnas.0832317100 PMC165875 Oliver, T. G. et al. Transcriptional profiling of the Sonic hedgehog response: a critical role for N-myc in proliferation of neuronal precursors. Proc. Natl Acad. Sci. USA 100 , 7331–7336 (2003). 10.1073/pnas.0832317100 PMC165875 12777630

94. Morrow D Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A Arterioscler Thromb. Vasc. Biol. 2009 29 1112 1118 19407245 10.1161/ATVBAHA.109.186890 PMC2794048 Morrow, D. et al. Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A. Arterioscler Thromb. Vasc. Biol. 29 , 1112–1118 (2009). 19407245 10.1161/ATVBAHA.109.186890 PMC2794048

95. Singh RR ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma Oncogene 2011 30 4874 4886 21625222 10.1038/onc.2011.195 PMC3165099 Singh, R. R. et al. ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma. Oncogene 30 , 4874–4886 (2011). 21625222 10.1038/onc.2011.195 PMC3165099

96. Teh MT FOXM1 is a downstream target of Gli1 in basal cell carcinomas Cancer Res. 2002 62 4773 4780 12183437 Teh, M. T. et al. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 62 , 4773–4780 (2002). 12183437

97. Macdonald R Midline signalling is required for Pax gene regulation and patterning of the eyes Development 1995 121 3267 3278 7588061 10.1242/dev.121.10.3267 Macdonald, R. et al. Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121 , 3267–3278 (1995). 7588061 10.1242/dev.121.10.3267

98. Katoh M Katoh M Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells Int. J. Mol. Med. 2006 17 681 685 16525728 Katoh, M. & Katoh, M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int. J. Mol. Med. 17 , 681–685 (2006). 16525728

99. Anvarian Z Cellular signalling by primary cilia in development, organ function and disease Nat. Rev. Nephrol. 2019 15 199 219 30733609 10.1038/s41581-019-0116-9 PMC6426138 Anvarian, Z. et al. Cellular signalling by primary cilia in development, organ function and disease. Nat. Rev. Nephrol. 15 , 199–219 (2019). 30733609 10.1038/s41581-019-0116-9 PMC6426138

100. Inglis P Boroevich K Leroux M Piecing together a ciliome Trends Genet. 2006 22 491 500 16860433 10.1016/j.tig.2006.07.006 Inglis, P., Boroevich, K. & Leroux, M. Piecing together a ciliome. Trends Genet. 22 , 491–500 (2006). 16860433 10.1016/j.tig.2006.07.006

101. Kim S Dynlacht B Assembling a primary cilium Curr. Opin. Cell Biol. 2013 25 506 511 23747070 10.1016/j.ceb.2013.04.011 PMC3729615 Kim, S. & Dynlacht, B. Assembling a primary cilium. Curr. Opin. Cell Biol. 25 , 506–511 (2013). 23747070 10.1016/j.ceb.2013.04.011 PMC3729615

102. Cui C Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome Dis. Model Mech. 2011 4 43 56 21045211 10.1242/dmm.006262 PMC3008963 Cui, C. et al. Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome. Dis. Model Mech. 4 , 43–56 (2011). 21045211 10.1242/dmm.006262 PMC3008963

103. Wang L Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding Nat. Commun. 2022 13 3997 35810181 10.1038/s41467-022-31751-0 PMC9271036 Wang, L. et al. Ciliary transition zone proteins coordinate ciliary protein composition and ectosome shedding. Nat. Commun. 13 , 3997 (2022). 35810181 10.1038/s41467-022-31751-0 PMC9271036

104. Webb S Mukhopadhyay A Roberts A Intraflagellar transport trains and motors: insights from structure Semin Cell Dev. Biol. 2020 107 82 90 32684327 10.1016/j.semcdb.2020.05.021 PMC7561706 Webb, S., Mukhopadhyay, A. & Roberts, A. Intraflagellar transport trains and motors: insights from structure. Semin Cell Dev. Biol. 107 , 82–90 (2020). 32684327 10.1016/j.semcdb.2020.05.021 PMC7561706

105. Ishida Y Tasaki K Katoh Y Nakayama K IFT52Molecular basis underlying the ciliary defects caused by variations found in skeletal ciliopathies Mol. Biol. Cell 2022 33 ar83 35704471 10.1091/mbc.E22-05-0188 PMC9582644 Ishida, Y., Tasaki, K., Katoh, Y. & Nakayama, K. IFT52Molecular basis underlying the ciliary defects caused by variations found in skeletal ciliopathies. Mol. Biol. Cell 33 , ar83 (2022). 35704471 10.1091/mbc.E22-05-0188 PMC9582644

106. Carpenter B Barry R Verhey K Allen B The heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function J. Cell Sci. 2015 128 1034 1050 25588831 10.1242/jcs.162552 PMC4342584 Carpenter, B., Barry, R., Verhey, K. & Allen, B. The heterotrimeric kinesin-2 complex interacts with and regulates GLI protein function. J. Cell Sci. 128 , 1034–1050 (2015). 25588831 10.1242/jcs.162552 PMC4342584

107. Pigino G Electron-tomographic analysis of intraflagellar transport particle trains in situ J. Cell Biol. 2009 187 135 148 19805633 10.1083/jcb.200905103 PMC2762096 Pigino, G. et al. Electron-tomographic analysis of intraflagellar transport particle trains in situ. J. Cell Biol. 187 , 135–148 (2009). 19805633 10.1083/jcb.200905103 PMC2762096

108. Wingfield J In vivo imaging shows continued association of several IFT-A, IFT-B and dynein complexes while IFT trains U-turn at the tip J. Cell Sci. 2021 134 jcs259010 34415027 10.1242/jcs.259010 PMC8487644 Wingfield, J. et al. In vivo imaging shows continued association of several IFT-A, IFT-B and dynein complexes while IFT trains U-turn at the tip. J. Cell Sci. 134 , jcs259010 (2021). 34415027 10.1242/jcs.259010 PMC8487644

109. Oswald F Prevo B Acar S Peterman E Interplay between ciliary ultrastructure and IFT-train dynamics revealed by single-molecule super-resolution imaging Cell Rep. 2018 25 224 235 30282031 10.1016/j.celrep.2018.09.019 Oswald, F., Prevo, B., Acar, S. & Peterman, E. Interplay between ciliary ultrastructure and IFT-train dynamics revealed by single-molecule super-resolution imaging. Cell Rep. 25 , 224–235 (2018). 30282031 10.1016/j.celrep.2018.09.019

110. Huangfu D Hedgehog signalling in the mouse requires intraflagellar transport proteins Nature 2003 426 83 87 14603322 10.1038/nature02061 Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426 , 83–87 (2003). 14603322 10.1038/nature02061

111. Pejskova P KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling J. Cell Biol. 2020 219 e201904107 32348467 10.1083/jcb.201904107 PMC7265313 Pejskova, P. et al. KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling. J. Cell Biol. 219 , e201904107 (2020). 32348467 10.1083/jcb.201904107 PMC7265313

112. Hildebrandt F Benzing T Katsanis N Ciliopathies N. Engl. J. Med. 2011 364 1533 1543 21506742 10.1056/NEJMra1010172 PMC3640822 Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364 , 1533–1543 (2011). 21506742 10.1056/NEJMra1010172 PMC3640822

113. Satir P Christensen S Overview of structure and function of mammalian cilia Annu Rev. Physiol. 2007 69 377 400 17009929 10.1146/annurev.physiol.69.040705.141236 Satir, P. & Christensen, S. Overview of structure and function of mammalian cilia. Annu Rev. Physiol. 69 , 377–400 (2007). 17009929 10.1146/annurev.physiol.69.040705.141236

114. Rohatgi R Milenkovic L Scott M Patched1 regulates hedgehog signaling at the primary cilium Science 2007 317 372 376 17641202 10.1126/science.1139740 Rohatgi, R., Milenkovic, L. & Scott, M. Patched1 regulates hedgehog signaling at the primary cilium. Science 317 , 372–376 (2007). 17641202 10.1126/science.1139740

115. Myers B Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response Dev. Cell 2013 26 346 357 23954590 10.1016/j.devcel.2013.07.015 PMC4196939 Myers, B. et al. Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev. Cell 26 , 346–357 (2013). 23954590 10.1016/j.devcel.2013.07.015 PMC4196939

116. Rohatgi R Milenkovic L Corcoran R Scott M Hedgehog signal transduction by smoothened: pharmacologic evidence for a 2-step activation process Proc. Natl Acad. Sci. USA 2009 106 3196 3201 19218434 10.1073/pnas.0813373106 PMC2642660 Rohatgi, R., Milenkovic, L., Corcoran, R. & Scott, M. Hedgehog signal transduction by smoothened: pharmacologic evidence for a 2-step activation process. Proc. Natl Acad. Sci. USA 106 , 3196–3201 (2009). 19218434 10.1073/pnas.0813373106 PMC2642660

117. Wang Y Zhou Z Walsh C McMahon A Selective translocation of intracellular smoothened to the primary cilium in response to Hedgehog pathway modulation Proc. Natl Acad. Sci. USA 2009 106 2623 2628 19196978 10.1073/pnas.0812110106 PMC2650314 Wang, Y., Zhou, Z., Walsh, C. & McMahon, A. Selective translocation of intracellular smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc. Natl Acad. Sci. USA 106 , 2623–2628 (2009). 19196978 10.1073/pnas.0812110106 PMC2650314

118. Wilson C Chen M Chuang P Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium PLoS One 2009 4 e5182 19365551 10.1371/journal.pone.0005182 PMC2664476 Wilson, C., Chen, M. & Chuang, P. Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS One 4 , e5182 (2009). 19365551 10.1371/journal.pone.0005182 PMC2664476

119. Goetz S Ocbina P Anderson K The primary cilium as a Hedgehog signal transduction machine Methods Cell Biol. 2009 94 199 222 20362092 10.1016/S0091-679X(08)94010-3 PMC2867239 Goetz, S., Ocbina, P. & Anderson, K. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol. 94 , 199–222 (2009). 20362092 10.1016/S0091-679X(08)94010-3 PMC2867239

120. Hirokawa N Tanaka Y Okada Y Cilia, KIF3 molecular motor and nodal flow Curr. Opin. Cell Biol. 2012 24 31 39 22285930 10.1016/j.ceb.2012.01.002 Hirokawa, N., Tanaka, Y. & Okada, Y. Cilia, KIF3 molecular motor and nodal flow. Curr. Opin. Cell Biol. 24 , 31–39 (2012). 22285930 10.1016/j.ceb.2012.01.002

121. Zhang J Liu Z Jia J Mechanisms of smoothened regulation in hedgehog signaling Cells 2021 10 2138 34440907 10.3390/cells10082138 PMC8391454 Zhang, J., Liu, Z. & Jia, J. Mechanisms of smoothened regulation in hedgehog signaling. Cells 10 , 2138 (2021). 34440907 10.3390/cells10082138 PMC8391454

122. Mukhopadhyay S Rohatgi R G-protein-coupled receptors, Hedgehog signaling and primary cilia Semin Cell Dev. Biol. 2014 33 63 72 24845016 10.1016/j.semcdb.2014.05.002 PMC4130902 Mukhopadhyay, S. & Rohatgi, R. G-protein-coupled receptors, Hedgehog signaling and primary cilia. Semin Cell Dev. Biol. 33 , 63–72 (2014). 24845016 10.1016/j.semcdb.2014.05.002 PMC4130902

123. Bachmann V Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling Proc. Natl Acad. Sci. USA 2016 113 7786 7791 27357676 10.1073/pnas.1608061113 PMC4948347 Bachmann, V. et al. Gpr161 anchoring of PKA consolidates GPCR and cAMP signaling. Proc. Natl Acad. Sci. USA 113 , 7786–7791 (2016). 27357676 10.1073/pnas.1608061113 PMC4948347

124. Cai E Zhang J Ge X Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium Sci. China Life Sci. 2022 65 500 514 34505970 10.1007/s11427-021-1975-9 PMC9132726 Cai, E., Zhang, J. & Ge, X. Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium. Sci. China Life Sci. 65 , 500–514 (2022). 34505970 10.1007/s11427-021-1975-9 PMC9132726

125. Truong M Vertebrate cells differentially interpret ciliary and extraciliary cAMP Cell 2021 184 2911 2926 33932338 10.1016/j.cell.2021.04.002 PMC8450001 Truong, M. et al. Vertebrate cells differentially interpret ciliary and extraciliary cAMP. Cell 184 , 2911–2926 (2021). 33932338 10.1016/j.cell.2021.04.002 PMC8450001

126. Pal K Mukhopadhyay S Primary cilium and sonic hedgehog signaling during neural tube patterning: role of GPCRs and second messengers Dev. Neurobiol. 2015 75 337 348 24863049 10.1002/dneu.22193 Pal, K. & Mukhopadhyay, S. Primary cilium and sonic hedgehog signaling during neural tube patterning: role of GPCRs and second messengers. Dev. Neurobiol. 75 , 337–348 (2015). 24863049 10.1002/dneu.22193

127. Happ J A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction Nat. Struct. Mol. Biol. 2022 29 990 999 36202993 10.1038/s41594-022-00838-z PMC9696579 Happ, J. et al. A PKA inhibitor motif within SMOOTHENED controls Hedgehog signal transduction. Nat. Struct. Mol. Biol. 29 , 990–999 (2022). 36202993 10.1038/s41594-022-00838-z PMC9696579

128. Liu Y The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling Sci. Signal 2014 7 ra117 25492966 10.1126/scisignal.2005608 Liu, Y. et al. The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling. Sci. Signal 7 , ra117 (2014). 25492966 10.1126/scisignal.2005608

129. He M The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment Nat. Cell Biol. 2014 16 663 672 24952464 10.1038/ncb2988 PMC4085576 He, M. et al. The kinesin-4 protein Kif7 regulates mammalian Hedgehog signalling by organizing the cilium tip compartment. Nat. Cell Biol. 16 , 663–672 (2014). 24952464 10.1038/ncb2988 PMC4085576

130. Villanueva H An essential role for Gα(i2) in smoothened-stimulated epithelial cell proliferation in the mammary gland Sci. Signal 2015 8 ra92 26373672 10.1126/scisignal.aaa7355 Villanueva, H. et al. An essential role for Gα(i2) in smoothened-stimulated epithelial cell proliferation in the mammary gland. Sci. Signal 8 , ra92 (2015). 26373672 10.1126/scisignal.aaa7355

131. Ogden S G protein Galphai functions immediately downstream of smoothened in Hedgehog signalling Nature 2008 456 967 970 18987629 10.1038/nature07459 PMC2744466 Ogden, S. et al. G protein Galphai functions immediately downstream of smoothened in Hedgehog signalling. Nature 456 , 967–970 (2008). 18987629 10.1038/nature07459 PMC2744466

132. Ogden S Genetic evidence for a Smoothened-Gα(i) signaling axis in mammals Sci. Signal 2015 8 fs16 26373671 10.1126/scisignal.aad0353 Ogden, S. Genetic evidence for a Smoothened-Gα(i) signaling axis in mammals. Sci. Signal 8 , fs16 (2015). 26373671 10.1126/scisignal.aad0353

133. Yang C Chen W Chen Y Jiang J Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2 Cell Res. 2012 22 1593 1604 22986504 10.1038/cr.2012.134 PMC3494391 Yang, C., Chen, W., Chen, Y. & Jiang, J. Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res. 22 , 1593–1604 (2012). 22986504 10.1038/cr.2012.134 PMC3494391

134. Endoh-Yamagami S The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development Curr. Biol. 2009 19 1320 1326 19592253 10.1016/j.cub.2009.06.046 Endoh-Yamagami, S. et al. The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr. Biol. 19 , 1320–1326 (2009). 19592253 10.1016/j.cub.2009.06.046

135. Raducu M SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development EMBO J. 2016 35 1400 1416 27234298 10.15252/embj.201593374 PMC4884786 Raducu, M. et al. SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. EMBO J. 35 , 1400–1416 (2016). 27234298 10.15252/embj.201593374 PMC4884786

136. Fokin Artem I Zhapparova Olga N Burakov Anton V Nadezhdina Elena S Centrosome-derived microtubule radial array, PCM-1 protein, and primary cilia formation Protoplasma 2019 256 1361 1373 31079229 10.1007/s00709-019-01385-z Fokin Artem, I., Zhapparova Olga, N., Burakov Anton, V. & Nadezhdina Elena, S. Centrosome-derived microtubule radial array, PCM-1 protein, and primary cilia formation. Protoplasma 256 , 1361–1373 (2019). 31079229 10.1007/s00709-019-01385-z

137. Li J PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant Dev. Biol. 2017 429 147 157 28673820 10.1016/j.ydbio.2017.06.035 PMC5831674 Li, J. et al. PKA-mediated Gli2 and Gli3 phosphorylation is inhibited by Hedgehog signaling in cilia and reduced in Talpid3 mutant. Dev. Biol. 429 , 147–157 (2017). 28673820 10.1016/j.ydbio.2017.06.035 PMC5831674

138. Fernandes-Silva H Correia-Pinto J Moura R Canonical sonic hedgehog signaling in early lung Dev. J. Dev. Biol. 2017 5 3 29615561 10.3390/jdb5010003 PMC5831770 Fernandes-Silva, H., Correia-Pinto, J. & Moura, R. Canonical sonic hedgehog signaling in early lung. Dev. J. Dev. Biol. 5 , 3 (2017). 29615561 10.3390/jdb5010003 PMC5831770

139. Washington Smoak I Sonic hedgehog is required for cardiac outflow tract and neural crest cell development Dev. Biol. 2005 283 357 372 15936751 10.1016/j.ydbio.2005.04.029 Washington Smoak, I. et al. Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev. Biol. 283 , 357–372 (2005). 15936751 10.1016/j.ydbio.2005.04.029

140. Jing D The vital role of Gli1 mesenchymal stem cells in tissue development and homeostasis J. Cell Physiol. 2021 236 6077 6089 33533019 10.1002/jcp.30310 Jing, D. et al. The vital role of Gli1 mesenchymal stem cells in tissue development and homeostasis. J. Cell Physiol. 236 , 6077–6089 (2021). 33533019 10.1002/jcp.30310

141. Petrova R Joyner A Roles for Hedgehog signaling in adult organ homeostasis and repair Development 2014 141 3445 3457 25183867 10.1242/dev.083691 PMC4197719 Petrova, R. & Joyner, A. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development 141 , 3445–3457 (2014). 25183867 10.1242/dev.083691 PMC4197719

142. Yang J Andre P Ye L Yang Y The Hedgehog signalling pathway in bone formation Int. J. Oral. Sci. 2015 7 73 79 26023726 10.1038/ijos.2015.14 PMC4817553 Yang, J., Andre, P., Ye, L. & Yang, Y. The Hedgehog signalling pathway in bone formation. Int. J. Oral. Sci. 7 , 73–79 (2015). 26023726 10.1038/ijos.2015.14 PMC4817553

143. Kimura H Ng J Curran T Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure Cancer Cell 2008 13 249 260 18328428 10.1016/j.ccr.2008.01.027 Kimura, H., Ng, J. & Curran, T. Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13 , 249–260 (2008). 18328428 10.1016/j.ccr.2008.01.027

144. Yang S Wang C The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis Bone 2012 51 407 417 22771375 10.1016/j.bone.2012.06.021 PMC3412883 Yang, S. & Wang, C. The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis. Bone 51 , 407–417 (2012). 22771375 10.1016/j.bone.2012.06.021 PMC3412883

145. Zou S Mesenchymal stem cells overexpressing Ihh promote bone repair J. Orthop. Surg. Res. 2014 9 102 25346272 10.1186/s13018-014-0102-7 PMC4213494 Zou, S. et al. Mesenchymal stem cells overexpressing Ihh promote bone repair. J. Orthop. Surg. Res. 9 , 102 (2014). 25346272 10.1186/s13018-014-0102-7 PMC4213494

146. Armstrong B Henner A Stewart S Stankunas K Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone Development 2017 144 1165 1176 28351866 10.1242/dev.143792 PMC5399624 Armstrong, B., Henner, A., Stewart, S. & Stankunas, K. Shh promotes direct interactions between epidermal cells and osteoblast progenitors to shape regenerated zebrafish bone. Development 144 , 1165–1176 (2017). 28351866 10.1242/dev.143792 PMC5399624

147. Zhao H The suture provides a niche for mesenchymal stem cells of craniofacial bones Nat. Cell Biol. 2015 17 386 396 25799059 10.1038/ncb3139 PMC4380556 Zhao, H. et al. The suture provides a niche for mesenchymal stem cells of craniofacial bones. Nat. Cell Biol. 17 , 386–396 (2015). 25799059 10.1038/ncb3139 PMC4380556

148. Shi Y Gli1 identifies osteogenic progenitors for bone formation and fracture repair Nat. Commun. 2017 8 2043 29230039 10.1038/s41467-017-02171-2 PMC5725597 Shi, Y. et al. Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat. Commun. 8 , 2043 (2017). 29230039 10.1038/s41467-017-02171-2 PMC5725597

149. Zhao H Chai Y Stem cells in teeth and craniofacial bones J. Dent. Res. 2015 94 1495 1501 26350960 10.1177/0022034515603972 PMC4622324 Zhao, H. & Chai, Y. Stem cells in teeth and craniofacial bones. J. Dent. Res. 94 , 1495–1501 (2015). 26350960 10.1177/0022034515603972 PMC4622324

150. Guo Y BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair Bone Res. 2018 6 30 30345151 10.1038/s41413-018-0031-x PMC6193039 Guo, Y. et al. BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair. Bone Res. 6 , 30 (2018). 30345151 10.1038/s41413-018-0031-x PMC6193039

151. Lepper C Partridge T Fan C An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration Development 2011 138 3639 3646 21828092 10.1242/dev.067595 PMC3152922 Lepper, C., Partridge, T. & Fan, C. An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138 , 3639–3646 (2011). 21828092 10.1242/dev.067595 PMC3152922

152. Yin H Price F Rudnicki M Satellite cells and the muscle stem cell niche Physiol. Rev. 2013 93 23 67 23303905 10.1152/physrev.00043.2011 PMC4073943 Yin, H., Price, F. & Rudnicki, M. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93 , 23–67 (2013). 23303905 10.1152/physrev.00043.2011 PMC4073943

153. Straface G Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration J. Cell Mol. Med. 2009 13 2424 2435 18662193 10.1111/j.1582-4934.2008.00440.x PMC3132885 Straface, G. et al. Sonic hedgehog regulates angiogenesis and myogenesis during post-natal skeletal muscle regeneration. J. Cell Mol. Med. 13 , 2424–2435 (2009). 18662193 10.1111/j.1582-4934.2008.00440.x PMC3132885

154. Koleva M Pleiotropic effects of sonic hedgehog on muscle satellite cells Cell Mol. Life Sci. 2005 62 1863 1870 16003493 10.1007/s00018-005-5072-9 PMC11139189 Koleva, M. et al. Pleiotropic effects of sonic hedgehog on muscle satellite cells. Cell Mol. Life Sci. 62 , 1863–1870 (2005). 16003493 10.1007/s00018-005-5072-9 PMC11139189

155. Elia D Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: involvement of MAPK/ERK and PI3K/Akt pathways Biochim. Biophys. Acta 2007 1773 1438 1446 17688959 10.1016/j.bbamcr.2007.06.006 Elia, D. et al. Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: involvement of MAPK/ERK and PI3K/Akt pathways. Biochim. Biophys. Acta 1773 , 1438–1446 (2007). 17688959 10.1016/j.bbamcr.2007.06.006

156. Madhala-Levy D Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity J. Cell Physiol. 2012 227 1455 1464 21618536 10.1002/jcp.22861 PMC3360966 Madhala-Levy, D. et al. Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity. J. Cell Physiol. 227 , 1455–1464 (2012). 21618536 10.1002/jcp.22861 PMC3360966

157. Anderson C Sonic hedgehog acts cell-autonomously on muscle precursor cells to generate limb muscle diversity Genes Dev. 2012 26 2103 2117 22987640 10.1101/gad.187807.112 PMC3444735 Anderson, C. et al. Sonic hedgehog acts cell-autonomously on muscle precursor cells to generate limb muscle diversity. Genes Dev. 26 , 2103–2117 (2012). 22987640 10.1101/gad.187807.112 PMC3444735

158. Voronova A Hedgehog signaling regulates MyoD expression and activity J. Biol. Chem. 2013 288 4389 4404 23266826 10.1074/jbc.M112.400184 PMC3567689 Voronova, A. et al. Hedgehog signaling regulates MyoD expression and activity. J. Biol. Chem. 288 , 4389–4404 (2013). 23266826 10.1074/jbc.M112.400184 PMC3567689

159. Devakanmalai G Zumrut H Ozbudak E Cited3 activates Mef2c to control muscle cell differentiation and survival Biol. Open 2013 2 505 514 23789100 10.1242/bio.20132550 PMC3654270 Devakanmalai, G., Zumrut, H. & Ozbudak, E. Cited3 activates Mef2c to control muscle cell differentiation and survival. Biol. Open 2 , 505–514 (2013). 23789100 10.1242/bio.20132550 PMC3654270

160. Kramann R Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease Cell Stem Cell 2016 19 628 642 27618218 10.1016/j.stem.2016.08.001 PMC5097006 Kramann, R. et al. Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease. Cell Stem Cell 19 , 628–642 (2016). 27618218 10.1016/j.stem.2016.08.001 PMC5097006

161. Boras-Granic K Chang H Grosschedl R Hamel P Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland Dev. Biol. 2006 295 219 231 16678815 10.1016/j.ydbio.2006.03.030 Boras-Granic, K., Chang, H., Grosschedl, R. & Hamel, P. Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland. Dev. Biol. 295 , 219–231 (2006). 16678815 10.1016/j.ydbio.2006.03.030

162. Sun X Coordinated hedgehog signaling induces new hair follicles in adult skin Elife 2020 9 e46756 32178760 10.7554/eLife.46756 PMC7077985 Sun, X. et al. Coordinated hedgehog signaling induces new hair follicles in adult skin. Elife 9 , e46756 (2020). 32178760 10.7554/eLife.46756 PMC7077985

163. Parisi M Lin H The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human Cell Res. 1998 8 15 21 9570013 10.1038/cr.1998.2 Parisi, M. & Lin, H. The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human. Cell Res. 8 , 15–21 (1998). 9570013 10.1038/cr.1998.2

164. Adolphe C An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis Development 2004 131 5009 5019 15371305 10.1242/dev.01367 Adolphe, C. et al. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Development 131 , 5009–5019 (2004). 15371305 10.1242/dev.01367

165. Zhou J Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis Hum. Reprod. 2006 21 1698 1704 16571640 10.1093/humrep/del086 Zhou, J. et al. Role of sonic hedgehog in maintaining a pool of proliferating stem cells in the human fetal epidermis. Hum. Reprod. 21 , 1698–1704 (2006). 16571640 10.1093/humrep/del086

166. Karlsson L Bondjers C Betsholtz C Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle Development 1999 126 2611 2621 10331973 10.1242/dev.126.12.2611 Karlsson, L., Bondjers, C. & Betsholtz, C. Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development 126 , 2611–2621 (1999). 10331973 10.1242/dev.126.12.2611

167. Oro A Higgins K Hair cycle regulation of Hedgehog signal reception Dev. Biol. 2003 255 238 248 12648487 10.1016/s0012-1606(02)00042-8 Oro, A. & Higgins, K. Hair cycle regulation of Hedgehog signal reception. Dev. Biol. 255 , 238–248 (2003). 12648487 10.1016/s0012-1606(02)00042-8

168. Vidal V Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment Curr. Biol. 2005 15 1340 1351 16085486 10.1016/j.cub.2005.06.064 Vidal, V. et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr. Biol. 15 , 1340–1351 (2005). 16085486 10.1016/j.cub.2005.06.064

169. Huelsken J beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin Cell 2001 105 533 545 11371349 10.1016/s0092-8674(01)00336-1 Huelsken, J. et al. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105 , 533–545 (2001). 11371349 10.1016/s0092-8674(01)00336-1

170. Santos A Lo Y Mah A Kuo C The intestinal stem cell niche: homeostasis and adaptations Trends Cell Biol. 2018 28 1062 1078 30195922 10.1016/j.tcb.2018.08.001 PMC6338454 Santos, A., Lo, Y., Mah, A. & Kuo, C. The intestinal stem cell niche: homeostasis and adaptations. Trends Cell Biol. 28 , 1062–1078 (2018). 30195922 10.1016/j.tcb.2018.08.001 PMC6338454

171. Kosinski C Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development Gastroenterology 2010 139 893 903 20542037 10.1053/j.gastro.2010.06.014 PMC2930094 Kosinski, C. et al. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 139 , 893–903 (2010). 20542037 10.1053/j.gastro.2010.06.014 PMC2930094

172. Degirmenci B GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells Nature 2018 558 449 453 29875413 10.1038/s41586-018-0190-3 Degirmenci, B. et al. GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature 558 , 449–453 (2018). 29875413 10.1038/s41586-018-0190-3

173. Coquenlorge S GLI2 modulated by SUFU and SPOP induces intestinal stem cell niche signals in development and tumorigenesis Cell Rep. 2019 27 3006 3018 31167144 10.1016/j.celrep.2019.05.016 Coquenlorge, S. et al. GLI2 modulated by SUFU and SPOP induces intestinal stem cell niche signals in development and tumorigenesis. Cell Rep. 27 , 3006–3018 (2019). 31167144 10.1016/j.celrep.2019.05.016

174. Xie Z Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease Cell Death Discov. 2021 7 314 34702800 10.1038/s41420-021-00679-7 PMC8548344 Xie, Z. et al. Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease. Cell Death Discov. 7 , 314 (2021). 34702800 10.1038/s41420-021-00679-7 PMC8548344

175. Lees C Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways PLoS Med. 2008 5 e239 19071955 10.1371/journal.pmed.0050239 PMC2596854 Lees, C. et al. Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways. PLoS Med. 5 , e239 (2008). 19071955 10.1371/journal.pmed.0050239 PMC2596854

176. van Dop W Loss of Indian Hedgehog activates multiple aspects of a wound healing response in the mouse intestine Gastroenterology 2010 139 1665 1676 20682322 10.1053/j.gastro.2010.07.045 van Dop, W. et al. Loss of Indian Hedgehog activates multiple aspects of a wound healing response in the mouse intestine. Gastroenterology 139 , 1665–1676 (2010). 1676.e1661-1610. 20682322 10.1053/j.gastro.2010.07.045

177. Westendorp B Indian Hedgehog suppresses a stromal cell-driven intestinal immune response Cell Mol. Gastroenterol. Hepatol. 2018 5 67 82 29276753 10.1016/j.jcmgh.2017.08.004 PMC5738458 Westendorp, B. et al. Indian Hedgehog suppresses a stromal cell-driven intestinal immune response. Cell Mol. Gastroenterol. Hepatol. 5 , 67–82 (2018). 29276753 10.1016/j.jcmgh.2017.08.004 PMC5738458

178. Lee J Control of inflammation by stromal Hedgehog pathway activation restrains colitis Proc. Natl Acad. Sci. USA 2016 113 E7545 E7553 27815529 10.1073/pnas.1616447113 PMC5127312 Lee, J. et al. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Proc. Natl Acad. Sci. USA 113 , E7545–E7553 (2016). 27815529 10.1073/pnas.1616447113 PMC5127312

179. Wang C Cassandras M Peng T The role of hedgehog signaling in adult lung regeneration and maintenance J. Dev. Biol. 2019 7 14 31323955 10.3390/jdb7030014 PMC6787692 Wang, C., Cassandras, M. & Peng, T. The role of hedgehog signaling in adult lung regeneration and maintenance. J. Dev. Biol. 7 , 14 (2019). 31323955 10.3390/jdb7030014 PMC6787692

180. Peng T Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration Nature 2015 526 578 582 26436454 10.1038/nature14984 PMC4713039 Peng, T. et al. Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration. Nature 526 , 578–582 (2015). 26436454 10.1038/nature14984 PMC4713039

181. Liu L Hedgehog signaling in neonatal and adult lung Am. J. Respir. Cell Mol. Biol. 2013 48 703 710 23371063 10.1165/rcmb.2012-0347OC PMC3727871 Liu, L. et al. Hedgehog signaling in neonatal and adult lung. Am. J. Respir. Cell Mol. Biol. 48 , 703–710 (2013). 23371063 10.1165/rcmb.2012-0347OC PMC3727871

182. Seidel K Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor Development 2010 137 3753 3761 20978073 10.1242/dev.056358 PMC3049275 Seidel, K. et al. Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor. Development 137 , 3753–3761 (2010). 20978073 10.1242/dev.056358 PMC3049275

183. Zhao H Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor Cell Stem Cell 2014 14 160 173 24506883 10.1016/j.stem.2013.12.013 PMC3951379 Zhao, H. et al. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14 , 160–173 (2014). 24506883 10.1016/j.stem.2013.12.013 PMC3951379

184. Men Y Gli1+ periodontium stem cells are regulated by osteocytes and occlusal force Dev. Cell 2020 54 639 654.e636 32652075 10.1016/j.devcel.2020.06.006 Men, Y. et al. Gli1+ periodontium stem cells are regulated by osteocytes and occlusal force. Dev. Cell 54 , 639–654.e636 (2020). 32652075 10.1016/j.devcel.2020.06.006

185. Sung H Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J. Clin. 2021 71 209 249 33538338 10.3322/caac.21660 Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71 , 209–249 (2021). 33538338 10.3322/caac.21660

186. Bach D Zhang W Sood A Chromosomal instability in tumor initiation and development Cancer Res. 2019 79 3995 4002 31350294 10.1158/0008-5472.CAN-18-3235 PMC7694409 Bach, D., Zhang, W. & Sood, A. Chromosomal instability in tumor initiation and development. Cancer Res. 79 , 3995–4002 (2019). 31350294 10.1158/0008-5472.CAN-18-3235 PMC7694409

187. Bajaj J Diaz E Reya T Stem cells in cancer initiation and progression J. Cell Biol. 2020 219 e201911053 31874116 10.1083/jcb.201911053 PMC7039188 Bajaj, J., Diaz, E. & Reya, T. Stem cells in cancer initiation and progression. J. Cell Biol. 219 , e201911053 (2020). 31874116 10.1083/jcb.201911053 PMC7039188

188. Zeng X Ju D Hedgehog signaling pathway and autophagy in cancer Int. J. Mol. Sci. 2018 19 2279 30081498 10.3390/ijms19082279 PMC6121518 Zeng, X. & Ju, D. Hedgehog signaling pathway and autophagy in cancer. Int. J. Mol. Sci. 19 , 2279 (2018). 30081498 10.3390/ijms19082279 PMC6121518

189. Hanna A Shevde L Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment Mol. Cancer 2016 15 24 26988232 10.1186/s12943-016-0509-3 PMC4797362 Hanna, A. & Shevde, L. Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. Mol. Cancer 15 , 24 (2016). 26988232 10.1186/s12943-016-0509-3 PMC4797362

190. Carballo G Honorato J de Lopes G Spohr T A highlight on sonic hedgehog pathway Cell Commun. Signal 2018 16 11 29558958 10.1186/s12964-018-0220-7 PMC5861627 Carballo, G., Honorato, J., de Lopes, G. & Spohr, T. A highlight on sonic hedgehog pathway. Cell Commun. Signal 16 , 11 (2018). 29558958 10.1186/s12964-018-0220-7 PMC5861627

191. Yang L Targeting cancer stem cell pathways for cancer therapy Signal Transduct. Target Ther. 2020 5 8 32296030 10.1038/s41392-020-0110-5 PMC7005297 Yang, L. et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target Ther. 5 , 8 (2020). 32296030 10.1038/s41392-020-0110-5 PMC7005297

192. Valkenburg KC de Groot AE Pienta KJ Targeting the tumour stroma to improve cancer therapy Nat. Rev. Clin. Oncol. 2018 15 366 381 29651130 10.1038/s41571-018-0007-1 PMC5960434 Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15 , 366–381 (2018). 29651130 10.1038/s41571-018-0007-1 PMC5960434

193. Ertao Z Autocrine sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway J. Exp. Clin. Cancer Res. 2016 35 63 27039174 10.1186/s13046-016-0336-9 PMC4818860 Ertao, Z. et al. Autocrine sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway. J. Exp. Clin. Cancer Res. 35 , 63 (2016). 27039174 10.1186/s13046-016-0336-9 PMC4818860

194. Singh S Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity Cancer Res. 2011 71 4454 4463 21565978 10.1158/0008-5472.CAN-10-2313 PMC3809996 Singh, S. et al. Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res. 71 , 4454–4463 (2011). 21565978 10.1158/0008-5472.CAN-10-2313 PMC3809996

195. Skoda AM The role of the Hedgehog signaling pathway in cancer: a comprehensive review Bosn. J. Basic Med. Sci. 2018 18 8 20 29274272 10.17305/bjbms.2018.2756 PMC5826678 Skoda, A. M. et al. The role of the Hedgehog signaling pathway in cancer: a comprehensive review. Bosn. J. Basic Med. Sci. 18 , 8–20 (2018). 29274272 10.17305/bjbms.2018.2756 PMC5826678

196. Yauch RL A paracrine requirement for hedgehog signalling in cancer Nature 2008 455 406 410 18754008 10.1038/nature07275 Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455 , 406–410 (2008). 18754008 10.1038/nature07275

197. Neville B Day T Oral cancer and precancerous lesions CA Cancer J. Clin. 2002 52 195 215 12139232 10.3322/canjclin.52.4.195 Neville, B. & Day, T. Oral cancer and precancerous lesions. CA Cancer J. Clin. 52 , 195–215 (2002). 12139232 10.3322/canjclin.52.4.195

198. Hasegawa M Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa Pathol. Res. Pract. 2016 212 426 436 26965914 10.1016/j.prp.2016.02.016 Hasegawa, M. et al. Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa. Pathol. Res. Pract. 212 , 426–436 (2016). 26965914 10.1016/j.prp.2016.02.016

199. Gonzalez A Immunohistochemical evaluation of hedgehog signalling in epithelial/mesenchymal interactions in squamous cell carcinoma transformation: a pilot study J. Oral. Pathol. Med. 2016 45 173 179 26947270 10.1111/jop.12346 Gonzalez, A. et al. Immunohistochemical evaluation of hedgehog signalling in epithelial/mesenchymal interactions in squamous cell carcinoma transformation: a pilot study. J. Oral. Pathol. Med. 45 , 173–179 (2016). 26947270 10.1111/jop.12346

200. Guimaraes V Hedgehog pathway activation in oral squamous cell carcinoma: cancer-associated fibroblasts exhibit nuclear GLI-1 localization J. Mol. Histol. 2020 51 675 684 33000351 10.1007/s10735-020-09913-5 Guimaraes, V. et al. Hedgehog pathway activation in oral squamous cell carcinoma: cancer-associated fibroblasts exhibit nuclear GLI-1 localization. J. Mol. Histol. 51 , 675–684 (2020). 33000351 10.1007/s10735-020-09913-5

201. Takabatake K The role of sonic hedgehog signaling in the tumor microenvironment of oral squamous cell carcinoma Int. J. Mol. Sci. 2019 20 5779 31744214 10.3390/ijms20225779 PMC6888610 Takabatake, K. et al. The role of sonic hedgehog signaling in the tumor microenvironment of oral squamous cell carcinoma. Int. J. Mol. Sci. 20 , 5779 (2019). 31744214 10.3390/ijms20225779 PMC6888610

202. Cierpikowski P Lis-Nawara A Bar J SHH expression is significantly associated with cancer stem cell markers in oral squamous cell carcinoma Anticancer Res. 2021 41 5405 5413 34732409 10.21873/anticanres.15352 Cierpikowski, P., Lis-Nawara, A. & Bar, J. SHH expression is significantly associated with cancer stem cell markers in oral squamous cell carcinoma. Anticancer Res. 41 , 5405–5413 (2021). 34732409 10.21873/anticanres.15352

203. Wang Y Expression of hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma Head Neck 2012 34 1556 1561 22287313 10.1002/hed.21958 Wang, Y. et al. Expression of hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma. Head Neck 34 , 1556–1561 (2012). 22287313 10.1002/hed.21958

204. Rodrigues M GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma Int. J. Oncol. 2018 53 2458 2472 30272273 10.3892/ijo.2018.4572 PMC6203148 Rodrigues, M. et al. GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma. Int. J. Oncol. 53 , 2458–2472 (2018). 30272273 10.3892/ijo.2018.4572 PMC6203148

205. Kuroda H Oral squamous cell carcinoma-derived sonic hedgehog promotes angiogenesis Anticancer Res. 2017 37 6731 6737 29187450 10.21873/anticanres.12132 Kuroda, H. et al. Oral squamous cell carcinoma-derived sonic hedgehog promotes angiogenesis. Anticancer Res. 37 , 6731–6737 (2017). 29187450 10.21873/anticanres.12132

206. Chen G Yan M Li R Chen W Sonic hedgehog signalling activation contributes to ALCAM over-expression and poor clinical outcome in patients with oral squamous cell carcinoma Chin. J. Dent. Res. 2018 21 31 40 29507910 10.3290/j.cjdr.a39916 Chen, G., Yan, M., Li, R. & Chen, W. Sonic hedgehog signalling activation contributes to ALCAM over-expression and poor clinical outcome in patients with oral squamous cell carcinoma. Chin. J. Dent. Res. 21 , 31–40 (2018). 29507910 10.3290/j.cjdr.a39916

207. Fan H Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression Med. Oncol. 2014 31 41 24915900 10.1007/s12032-014-0041-5 Fan, H. et al. Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression. Med. Oncol. 31 , 41 (2014). 24915900 10.1007/s12032-014-0041-5

208. Shear M Odontogenic keratocysts: clinical features Oral. Maxillofac. Surg. Clin. North Am. 2003 15 335 345 18088687 10.1016/S1042-3699(03)00035-9 Shear, M. Odontogenic keratocysts: clinical features. Oral. Maxillofac. Surg. Clin. North Am. 15 , 335–345 (2003). 18088687 10.1016/S1042-3699(03)00035-9

209. Hashmi A Mutiple keratocystic odontogenic tumors (KCOT) in a patient with Gorlin syndrome: a case report with late presentation and absence of skin manifestations BMC Res. Notes 2016 9 357 27448602 10.1186/s13104-016-2166-4 PMC4957855 Hashmi, A. et al. Mutiple keratocystic odontogenic tumors (KCOT) in a patient with Gorlin syndrome: a case report with late presentation and absence of skin manifestations. BMC Res. Notes 9 , 357 (2016). 27448602 10.1186/s13104-016-2166-4 PMC4957855

210. Gorlin R Goltz R Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome N. Engl. J. Med. 1960 262 908 912 13851319 10.1056/NEJM196005052621803 Gorlin, R. & Goltz, R. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N. Engl. J. Med. 262 , 908–912 (1960). 13851319 10.1056/NEJM196005052621803

211. Onodera S Nakamura Y Azuma T Gorlin syndrome: recent advances in genetic testing and molecular and cellular biological research Int. J. Mol. Sci. 2020 21 7559 33066274 10.3390/ijms21207559 PMC7590212 Onodera, S., Nakamura, Y. & Azuma, T. Gorlin syndrome: recent advances in genetic testing and molecular and cellular biological research. Int. J. Mol. Sci. 21 , 7559 (2020). 33066274 10.3390/ijms21207559 PMC7590212

212. Qu J Underestimated PTCH1 mutation rate in sporadic keratocystic odontogenic tumors Oral. Oncol. 2015 51 40 45 25458233 10.1016/j.oraloncology.2014.09.016 Qu, J. et al. Underestimated PTCH1 mutation rate in sporadic keratocystic odontogenic tumors. Oral. Oncol. 51 , 40–45 (2015). 25458233 10.1016/j.oraloncology.2014.09.016

213. Stojanov I Biallelic PTCH1 inactivation is a dominant genomic change in sporadic keratocystic odontogenic tumors Am. J. Surg. Pathol. 2020 44 553 560 31725470 10.1097/PAS.0000000000001407 PMC7071995 Stojanov, I. et al. Biallelic PTCH1 inactivation is a dominant genomic change in sporadic keratocystic odontogenic tumors. Am. J. Surg. Pathol. 44 , 553–560 (2020). 31725470 10.1097/PAS.0000000000001407 PMC7071995

214. Yu F The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome Int. J. Mol. Med. 2014 34 507 512 24840883 10.3892/ijmm.2014.1783 Yu, F. et al. The large intracellular loop of ptch1 mediates the non-canonical Hedgehog pathway through cyclin B1 in nevoid basal cell carcinoma syndrome. Int. J. Mol. Med. 34 , 507–512 (2014). 24840883 10.3892/ijmm.2014.1783

215. Barreto D Bale A De Marco L Gomez R Immunolocalization of PTCH protein in odontogenic cysts and tumors J. Dent. Res. 2002 81 757 760 12407090 10.1177/0810757 Barreto, D., Bale, A., De Marco, L. & Gomez, R. Immunolocalization of PTCH protein in odontogenic cysts and tumors. J. Dent. Res. 81 , 757–760 (2002). 12407090 10.1177/0810757

216. Ohki K PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts Int. J. Oral. Maxillofac. Surg. 2004 33 584 592 15308259 10.1016/j.ijom.2004.01.013 Ohki, K. et al. PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. Int. J. Oral. Maxillofac. Surg. 33 , 584–592 (2004). 15308259 10.1016/j.ijom.2004.01.013

217. Grachtchouk M Odontogenic keratocysts arise from quiescent epithelial rests and are associated with deregulated hedgehog signaling in mice and humans Am. J. Pathol. 2006 169 806 814 16936257 10.2353/ajpath.2006.060054 PMC1698812 Grachtchouk, M. et al. Odontogenic keratocysts arise from quiescent epithelial rests and are associated with deregulated hedgehog signaling in mice and humans. Am. J. Pathol. 169 , 806–814 (2006). 16936257 10.2353/ajpath.2006.060054 PMC1698812

218. Gurgel C Transcriptional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma J. Oral. Pathol. Med. 2014 43 619 626 24930892 10.1111/jop.12180 Gurgel, C. et al. Transcriptional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma. J. Oral. Pathol. Med. 43 , 619–626 (2014). 24930892 10.1111/jop.12180

219. Hoyos Cadavid A Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts Clin. Oral. Investig. 2019 23 153 159 29564556 10.1007/s00784-018-2421-2 Hoyos Cadavid, A. et al. Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts. Clin. Oral. Investig. 23 , 153–159 (2019). 29564556 10.1007/s00784-018-2421-2

220. Yagyuu T Recurrence of keratocystic odontogenic tumor: clinicopathological features and immunohistochemical study of the Hedgehog signaling pathway Pathobiology 2008 75 171 176 18550914 10.1159/000124977 Yagyuu, T. et al. Recurrence of keratocystic odontogenic tumor: clinicopathological features and immunohistochemical study of the Hedgehog signaling pathway. Pathobiology 75 , 171–176 (2008). 18550914 10.1159/000124977

221. Li X The role of Shh signalling pathway in central nervous system development and related diseases Cell Biochem. Funct. 2021 39 180 189 32840890 10.1002/cbf.3582 Li, X. et al. The role of Shh signalling pathway in central nervous system development and related diseases. Cell Biochem. Funct. 39 , 180–189 (2021). 32840890 10.1002/cbf.3582

222. Rolland A Aquilina K Surgery for recurrent medulloblastoma: a review Neurochirurgie 2021 67 69 75 31351079 10.1016/j.neuchi.2019.06.008 Rolland, A. & Aquilina, K. Surgery for recurrent medulloblastoma: a review. Neurochirurgie 67 , 69–75 (2021). 31351079 10.1016/j.neuchi.2019.06.008

223. Garcia-Lopez J Kumar R Smith K Northcott P Deconstructing sonic hedgehog medulloblastoma: molecular subtypes, drivers, and beyond Trends Genet. 2021 37 235 250 33272592 10.1016/j.tig.2020.11.001 Garcia-Lopez, J., Kumar, R., Smith, K. & Northcott, P. Deconstructing sonic hedgehog medulloblastoma: molecular subtypes, drivers, and beyond. Trends Genet. 37 , 235–250 (2021). 33272592 10.1016/j.tig.2020.11.001

224. Chen L O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling Proc. Natl Acad. Sci. USA 2022 119 e2202821119 35969743 10.1073/pnas.2202821119 PMC9407465 Chen, L. et al. O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling. Proc. Natl Acad. Sci. USA 119 , e2202821119 (2022). 35969743 10.1073/pnas.2202821119 PMC9407465

225. Kumar V Challenges and recent advances in medulloblastoma therapy Trends Pharmacol. Sci. 2017 38 1061 1084 29061299 10.1016/j.tips.2017.09.002 Kumar, V. et al. Challenges and recent advances in medulloblastoma therapy. Trends Pharmacol. Sci. 38 , 1061–1084 (2017). 29061299 10.1016/j.tips.2017.09.002

226. Northcott P Medulloblastomics: the end of the beginning Nat. Rev. Cancer 2012 12 818 834 23175120 10.1038/nrc3410 PMC3889646 Northcott, P. et al. Medulloblastomics: the end of the beginning. Nat. Rev. Cancer 12 , 818–834 (2012). 23175120 10.1038/nrc3410 PMC3889646

227. Kool M Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition Cancer Cell 2014 25 393 405 24651015 10.1016/j.ccr.2014.02.004 PMC4493053 Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25 , 393–405 (2014). 24651015 10.1016/j.ccr.2014.02.004 PMC4493053

228. Yang Z Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells Cancer Cell 2008 14 135 145 18691548 10.1016/j.ccr.2008.07.003 PMC2538687 Yang, Z. et al. Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 14 , 135–145 (2008). 18691548 10.1016/j.ccr.2008.07.003 PMC2538687

229. Selvadurai H Medulloblastoma arises from the persistence of a rare and transient Sox2 granule neuron precursor Cell Rep. 2020 31 107511 32294450 10.1016/j.celrep.2020.03.075 Selvadurai, H. et al. Medulloblastoma arises from the persistence of a rare and transient Sox2 granule neuron precursor. Cell Rep. 31 , 107511 (2020). 32294450 10.1016/j.celrep.2020.03.075

230. Liu Y Astrocytes promote medulloblastoma progression through hedgehog secretion Cancer Res. 2017 77 6692 6703 28986380 10.1158/0008-5472.CAN-17-1463 PMC5759326 Liu, Y. et al. Astrocytes promote medulloblastoma progression through hedgehog secretion. Cancer Res. 77 , 6692–6703 (2017). 28986380 10.1158/0008-5472.CAN-17-1463 PMC5759326

231. Kieran M Targeted treatment for sonic hedgehog-dependent medulloblastoma Neuro Oncol. 2014 16 1037 1047 24951114 10.1093/neuonc/nou109 PMC4096181 Kieran, M. Targeted treatment for sonic hedgehog-dependent medulloblastoma. Neuro Oncol. 16 , 1037–1047 (2014). 24951114 10.1093/neuonc/nou109 PMC4096181

232. Vanner R Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma Cancer Cell 2014 26 33 47 24954133 10.1016/j.ccr.2014.05.005 PMC4441014 Vanner, R. et al. Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell 26 , 33–47 (2014). 24954133 10.1016/j.ccr.2014.05.005 PMC4441014

233. Fine H Malignant gliomas: simplifying the complexity Cancer Discov. 2019 9 1650 1652 31792122 10.1158/2159-8290.CD-19-1081 Fine, H. Malignant gliomas: simplifying the complexity. Cancer Discov. 9 , 1650–1652 (2019). 31792122 10.1158/2159-8290.CD-19-1081

234. Mittal S Pradhan S Srivastava T Recent advances in targeted therapy for glioblastoma Expert Rev. Neurother. 2015 15 935 946 26118735 10.1586/14737175.2015.1061934 Mittal, S., Pradhan, S. & Srivastava, T. Recent advances in targeted therapy for glioblastoma. Expert Rev. Neurother. 15 , 935–946 (2015). 26118735 10.1586/14737175.2015.1061934

235. Cherepanov S Effect of hedgehog signaling pathway activation on proliferation of high-grade gliomas Bull. Exp. Biol. Med. 2016 161 674 678 27709388 10.1007/s10517-016-3483-2 Cherepanov, S. et al. Effect of hedgehog signaling pathway activation on proliferation of high-grade gliomas. Bull. Exp. Biol. Med. 161 , 674–678 (2016). 27709388 10.1007/s10517-016-3483-2

236. Henao-Restrepo J Expression of activator proteins of SHH/GLI and PI3K/Akt/mTORC1 signaling pathways in human gliomas is associated with high grade tumors Exp. Mol. Pathol. 2021 122 104673 34371011 10.1016/j.yexmp.2021.104673 Henao-Restrepo, J. et al. Expression of activator proteins of SHH/GLI and PI3K/Akt/mTORC1 signaling pathways in human gliomas is associated with high grade tumors. Exp. Mol. Pathol. 122 , 104673 (2021). 34371011 10.1016/j.yexmp.2021.104673

237. Wang H Hedgehog signaling regulates the development and treatment of glioblastoma Oncol. Lett. 2022 24 294 35949611 10.3892/ol.2022.13414 PMC9353242 Wang, H. et al. Hedgehog signaling regulates the development and treatment of glioblastoma. Oncol. Lett. 24 , 294 (2022). 35949611 10.3892/ol.2022.13414 PMC9353242

238. Torrisi F Connexin 43 and sonic hedgehog pathway interplay in glioblastoma cell proliferation and migration Biol. (Basel) 2021 10 767 10.3390/biology10080767 PMC8389699 34439999 Torrisi, F. et al. Connexin 43 and sonic hedgehog pathway interplay in glioblastoma cell proliferation and migration. Biol. (Basel) 10 , 767 (2021). 10.3390/biology10080767 PMC8389699 34439999

239. Chang L Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma Mol. Med. Rep. 2015 12 6702 6710 26299938 10.3892/mmr.2015.4229 PMC4626128 Chang, L. et al. Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma. Mol. Med. Rep. 12 , 6702–6710 (2015). 26299938 10.3892/mmr.2015.4229 PMC4626128

240. Jiang K Fms related tyrosine kinase 1 (Flt1) functions as an oncogene and regulates glioblastoma cell metastasis by regulating sonic hedgehog signaling Am. J. Cancer Res. 2017 7 1164 1176 28560064 PMC5446481 Jiang, K. et al. Fms related tyrosine kinase 1 (Flt1) functions as an oncogene and regulates glioblastoma cell metastasis by regulating sonic hedgehog signaling. Am. J. Cancer Res. 7 , 1164–1176 (2017). 28560064 PMC5446481

241. Shahi M Lorente A Castresana J Hedgehog signalling in medulloblastoma, glioblastoma and neuroblastoma Oncol. Rep. 2008 19 681 688 18288402 Shahi, M., Lorente, A. & Castresana, J. Hedgehog signalling in medulloblastoma, glioblastoma and neuroblastoma. Oncol. Rep. 19 , 681–688 (2008). 18288402

242. Chen S HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling PloS One 2015 10 e0121115 25811359 10.1371/journal.pone.0121115 PMC4374675 Chen, S. et al. HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling. PloS One 10 , e0121115 (2015). 25811359 10.1371/journal.pone.0121115 PMC4374675

243. Souzaki R Hedgehog signaling pathway in neuroblastoma differentiation J. Pediatr. Surg. 2010 45 2299 2304 21129534 10.1016/j.jpedsurg.2010.08.020 Souzaki, R. et al. Hedgehog signaling pathway in neuroblastoma differentiation. J. Pediatr. Surg. 45 , 2299–2304 (2010). 21129534 10.1016/j.jpedsurg.2010.08.020

244. Xu L Sonic Hedgehog pathway is essential for neuroblastoma cell proliferation and tumor growth Mol. Cell Biochem. 2012 364 235 241 22350753 10.1007/s11010-011-1222-6 Xu, L. et al. Sonic Hedgehog pathway is essential for neuroblastoma cell proliferation and tumor growth. Mol. Cell Biochem. 364 , 235–241 (2012). 22350753 10.1007/s11010-011-1222-6

245. Koeniger A Activation of cilia-independent hedgehog/GLI1 signaling as a novel concept for neuroblastoma therapy Cancers (Basel) 2021 13 1908 33921042 10.3390/cancers13081908 PMC8071409 Koeniger, A. et al. Activation of cilia-independent hedgehog/GLI1 signaling as a novel concept for neuroblastoma therapy. Cancers (Basel) 13 , 1908 (2021). 33921042 10.3390/cancers13081908 PMC8071409

246. Siegel R Miller K Fuchs H Jemal A Cancer statistics, 2021 CA Cancer J. Clin. 2021 71 7 33 33433946 10.3322/caac.21654 Siegel, R., Miller, K., Fuchs, H. & Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 71 , 7–33 (2021). 33433946 10.3322/caac.21654

247. Signoretti S Flaifel A Chen Y Reuter V Renal cell carcinoma in the era of precision medicine: from molecular pathology to tissue-based biomarkers J. Clin. Oncol. 2018 36 JCO2018792259 30372384 10.1200/JCO.2018.79.2259 PMC6299340 Signoretti, S., Flaifel, A., Chen, Y. & Reuter, V. Renal cell carcinoma in the era of precision medicine: from molecular pathology to tissue-based biomarkers. J. Clin. Oncol. 36 , JCO2018792259 (2018). 30372384 10.1200/JCO.2018.79.2259 PMC6299340

248. Dormoy V The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth Mol. Cancer 2009 8 123 20015350 10.1186/1476-4598-8-123 PMC2803450 Dormoy, V. et al. The sonic hedgehog signaling pathway is reactivated in human renal cell carcinoma and plays orchestral role in tumor growth. Mol. Cancer 8 , 123 (2009). 20015350 10.1186/1476-4598-8-123 PMC2803450

249. Kotulak-Chrzaszcz A Expression of the Sonic Hedgehog pathway components in clear cell renal cell carcinoma Oncol. Lett. 2019 18 5801 5810 31788053 10.3892/ol.2019.10919 PMC6865145 Kotulak-Chrzaszcz, A. et al. Expression of the Sonic Hedgehog pathway components in clear cell renal cell carcinoma. Oncol. Lett. 18 , 5801–5810 (2019). 31788053 10.3892/ol.2019.10919 PMC6865145

250. Jäger W DHH is an independent prognosticator of oncologic outcome of clear cell renal cell carcinoma J. Urol. 2014 192 1842 1848 25046620 10.1016/j.juro.2014.07.013 Jäger, W. et al. DHH is an independent prognosticator of oncologic outcome of clear cell renal cell carcinoma. J. Urol. 192 , 1842–1848 (2014). 25046620 10.1016/j.juro.2014.07.013

251. D’Amato C Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells Br. J. Cancer 2014 111 1168 1179 25093491 10.1038/bjc.2014.421 PMC4453852 D’Amato, C. et al. Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells. Br. J. Cancer 111 , 1168–1179 (2014). 25093491 10.1038/bjc.2014.421 PMC4453852

252. Dormoy V Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma Carcinogenesis 2012 33 2084 2093 22843547 10.1093/carcin/bgs255 Dormoy, V. et al. Vitamin D3 triggers antitumor activity through targeting hedgehog signaling in human renal cell carcinoma. Carcinogenesis 33 , 2084–2093 (2012). 22843547 10.1093/carcin/bgs255

253. Behnsawy H Possible role of sonic hedgehog and epithelial-mesenchymal transition in renal cell cancer progression Korean J. Urol. 2013 54 547 554 23956832 10.4111/kju.2013.54.8.547 PMC3742909 Behnsawy, H. et al. Possible role of sonic hedgehog and epithelial-mesenchymal transition in renal cell cancer progression. Korean J. Urol. 54 , 547–554 (2013). 23956832 10.4111/kju.2013.54.8.547 PMC3742909

254. Zhou J Reciprocal regulation of hypoxia-inducible factor 2α and GLI1 expression associated with the radioresistance of renal cell carcinoma Int. J. Radiat. Oncol. Biol. Phys. 2014 90 942 951 25585786 10.1016/j.ijrobp.2014.06.065 Zhou, J. et al. Reciprocal regulation of hypoxia-inducible factor 2α and GLI1 expression associated with the radioresistance of renal cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 90 , 942–951 (2014). 25585786 10.1016/j.ijrobp.2014.06.065

255. Furukawa J Miyake H Fujisawa M GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib Mol. Clin. Oncol. 2016 5 186 192 27602218 10.3892/mco.2016.950 PMC4998152 Furukawa, J., Miyake, H. & Fujisawa, M. GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib. Mol. Clin. Oncol. 5 , 186–192 (2016). 27602218 10.3892/mco.2016.950 PMC4998152

256. Hyuga T Hedgehog signaling for urogenital organogenesis and prostate cancer: an implication for the epithelial-mesenchyme interaction (EMI) Int. J. Mol. Sci. 2019 21 58 31861793 10.3390/ijms21010058 PMC6982176 Hyuga, T. et al. Hedgehog signaling for urogenital organogenesis and prostate cancer: an implication for the epithelial-mesenchyme interaction (EMI). Int. J. Mol. Sci. 21 , 58 (2019). 31861793 10.3390/ijms21010058 PMC6982176

257. Odero-Marah V Hawsawi O Henderson V Sweeney J Epithelial-mesenchymal transition (EMT) and prostate cancer Adv. Exp. Med. Biol. 2018 1095 101 110 30229551 10.1007/978-3-319-95693-0_6 Odero-Marah, V., Hawsawi, O., Henderson, V. & Sweeney, J. Epithelial-mesenchymal transition (EMT) and prostate cancer. Adv. Exp. Med. Biol. 1095 , 101–110 (2018). 30229551 10.1007/978-3-319-95693-0_6

258. Wilkinson S Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium Prostate 2013 73 1810 1823 24105601 10.1002/pros.22720 Wilkinson, S. et al. Hedgehog signaling is active in human prostate cancer stroma and regulates proliferation and differentiation of adjacent epithelium. Prostate 73 , 1810–1823 (2013). 24105601 10.1002/pros.22720

259. Sanchez P Inhibition of prostate cancer proliferation by interference with Sonic Hedgehog-GLI1 signaling Proc. Natl Acad. Sci. USA 2004 101 12561 12566 15314219 10.1073/pnas.0404956101 PMC514658 Sanchez, P. et al. Inhibition of prostate cancer proliferation by interference with Sonic Hedgehog-GLI1 signaling. Proc. Natl Acad. Sci. USA 101 , 12561–12566 (2004). 15314219 10.1073/pnas.0404956101 PMC514658

260. Kim T Hedgehog signaling protein expression and its association with prognostic parameters in prostate cancer: a retrospective study from the view point of new 2010 anatomic stage/prognostic groups J. Surg. Oncol. 2011 104 472 479 21656527 10.1002/jso.21988 Kim, T. et al. Hedgehog signaling protein expression and its association with prognostic parameters in prostate cancer: a retrospective study from the view point of new 2010 anatomic stage/prognostic groups. J. Surg. Oncol. 104 , 472–479 (2011). 21656527 10.1002/jso.21988

261. Sheng T Activation of the hedgehog pathway in advanced prostate cancer Mol. Cancer 2004 3 29 15482598 10.1186/1476-4598-3-29 PMC524523 Sheng, T. et al. Activation of the hedgehog pathway in advanced prostate cancer. Mol. Cancer 3 , 29 (2004). 15482598 10.1186/1476-4598-3-29 PMC524523

262. Chang H Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model J. Biomed. Sci. 2011 18 6 21241512 10.1186/1423-0127-18-6 PMC3025942 Chang, H. et al. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. J. Biomed. Sci. 18 , 6 (2011). 21241512 10.1186/1423-0127-18-6 PMC3025942

263. Acikgoz E Sonic hedgehog signaling is associated with resistance to zoledronic acid in CD133high/CD44high prostate cancer stem cells Mol. Biol. Rep. 2021 48 3567 3578 33948856 10.1007/s11033-021-06387-w Acikgoz, E. et al. Sonic hedgehog signaling is associated with resistance to zoledronic acid in CD133high/CD44high prostate cancer stem cells. Mol. Biol. Rep. 48 , 3567–3578 (2021). 33948856 10.1007/s11033-021-06387-w

264. Cai H Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma Tumour Biol. 2016 37 16199 16205 10.1007/s13277-016-5463-6 27744627 Cai, H. et al. Sonic hedgehog signaling pathway mediates development of hepatocellular carcinoma. Tumour Biol. 37 , 16199–16205 (2016). 10.1007/s13277-016-5463-6 27744627

265. Machado M Diehl A Hedgehog signalling in liver pathophysiology J. Hepatol. 2018 68 550 562 29107151 10.1016/j.jhep.2017.10.017 PMC5957514 Machado, M. & Diehl, A. Hedgehog signalling in liver pathophysiology. J. Hepatol. 68 , 550–562 (2018). 29107151 10.1016/j.jhep.2017.10.017 PMC5957514

266. Dugum M Sonic hedgehog signaling in hepatocellular carcinoma: a pilot study Mol. Clin. Oncol. 2016 4 369 374 26998285 10.3892/mco.2016.728 PMC4774427 Dugum, M. et al. Sonic hedgehog signaling in hepatocellular carcinoma: a pilot study. Mol. Clin. Oncol. 4 , 369–374 (2016). 26998285 10.3892/mco.2016.728 PMC4774427

267. Sicklick J Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis Carcinogenesis 2006 27 748 757 16339184 10.1093/carcin/bgi292 Sicklick, J. et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27 , 748–757 (2006). 16339184 10.1093/carcin/bgi292

268. Jeng K High expression of patched homolog-1 messenger RNA and glioma-associated oncogene-1 messenger RNA of sonic hedgehog signaling pathway indicates a risk of postresection recurrence of hepatocellular carcinoma Ann. Surg. Oncol. 2013 20 464 473 22911366 10.1245/s10434-012-2593-y Jeng, K. et al. High expression of patched homolog-1 messenger RNA and glioma-associated oncogene-1 messenger RNA of sonic hedgehog signaling pathway indicates a risk of postresection recurrence of hepatocellular carcinoma. Ann. Surg. Oncol. 20 , 464–473 (2013). 22911366 10.1245/s10434-012-2593-y

269. Chen J Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer Carcinogenesis 2013 34 10 19 22948179 10.1093/carcin/bgs274 Chen, J. et al. Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. Carcinogenesis 34 , 10–19 (2013). 22948179 10.1093/carcin/bgs274

270. Fan Y Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells Oncogene 2016 35 116 124 25772244 10.1038/onc.2015.67 Fan, Y. et al. Aberrant hedgehog signaling is responsible for the highly invasive behavior of a subpopulation of hepatoma cells. Oncogene 35 , 116–124 (2016). 25772244 10.1038/onc.2015.67

271. Chen X Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations J. Hepatol. 2011 55 838 845 21334406 10.1016/j.jhep.2010.12.043 PMC3177032 Chen, X. et al. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J. Hepatol. 55 , 838–845 (2011). 21334406 10.1016/j.jhep.2010.12.043 PMC3177032

272. Yamada S Epithelial to mesenchymal transition is associated with shorter disease-free survival in hepatocellular carcinoma Ann. Surg. Oncol. 2014 21 3882 3890 24833103 10.1245/s10434-014-3779-2 Yamada, S. et al. Epithelial to mesenchymal transition is associated with shorter disease-free survival in hepatocellular carcinoma. Ann. Surg. Oncol. 21 , 3882–3890 (2014). 24833103 10.1245/s10434-014-3779-2

273. Wang S Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids J. Exp. Clin. Cancer Res. 2020 39 22 31992334 10.1186/s13046-020-1523-2 PMC6986013 Wang, S. et al. Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids. J. Exp. Clin. Cancer Res. 39 , 22 (2020). 31992334 10.1186/s13046-020-1523-2 PMC6986013

274. Zhou X Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma J. Cell Mol. Med. 2020 24 4298 4311 32108992 10.1111/jcmm.15090 PMC7171417 Zhou, X. et al. Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma. J. Cell Mol. Med. 24 , 4298–4311 (2020). 32108992 10.1111/jcmm.15090 PMC7171417

275. Razumilava N Gores G Cholangiocarcinoma Lancet 2014 383 2168 2179 24581682 10.1016/S0140-6736(13)61903-0 PMC4069226 Razumilava, N. & Gores, G. Cholangiocarcinoma. Lancet 383 , 2168–2179 (2014). 24581682 10.1016/S0140-6736(13)61903-0 PMC4069226

276. Riedlinger D Hedgehog pathway as a potential treatment target in human cholangiocarcinoma J. Hepatobiliary Pancreat. Sci. 2014 21 607 615 24733827 10.1002/jhbp.107 Riedlinger, D. et al. Hedgehog pathway as a potential treatment target in human cholangiocarcinoma. J. Hepatobiliary Pancreat. Sci. 21 , 607–615 (2014). 24733827 10.1002/jhbp.107

277. Anichini G The Role of the Hedgehog Pathway in Cholangiocarcinoma Cancers (Basel) 2021 13 4774 34638259 10.3390/cancers13194774 PMC8507550 Anichini, G. et al. The Role of the Hedgehog Pathway in Cholangiocarcinoma. Cancers (Basel) 13 , 4774 (2021). 34638259 10.3390/cancers13194774 PMC8507550

278. Tang L The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma Clin. Cancer Res. 2013 19 2014 2024 23493353 10.1158/1078-0432.CCR-12-0349 Tang, L. et al. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin. Cancer Res. 19 , 2014–2024 (2013). 23493353 10.1158/1078-0432.CCR-12-0349

279. Jing X Role of hypoxia in cancer therapy by regulating the tumor microenvironment Mol. Cancer 2019 18 157 31711497 10.1186/s12943-019-1089-9 PMC6844052 Jing, X. et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol. Cancer 18 , 157 (2019). 31711497 10.1186/s12943-019-1089-9 PMC6844052

280. Bhuria V Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma Exp. Cell Res. 2019 385 111671 31634481 10.1016/j.yexcr.2019.111671 Bhuria, V. et al. Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma. Exp. Cell Res. 385 , 111671 (2019). 31634481 10.1016/j.yexcr.2019.111671

281. Kim Y Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma Ann. Surg. Oncol. 2014 21 2684 2698 24682719 10.1245/s10434-014-3531-y Kim, Y. et al. Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. Ann. Surg. Oncol. 21 , 2684–2698 (2014). 24682719 10.1245/s10434-014-3531-y

282. Chen Z SHH/GLI2-TGF-β1 feedback loop between cancer cells and tumor-associated macrophages maintains epithelial-mesenchymal transition and endoplasmic reticulum homeostasis in cholangiocarcinoma Pharmacol. Res. 2023 187 106564 36423790 10.1016/j.phrs.2022.106564 Chen, Z. et al. SHH/GLI2-TGF-β1 feedback loop between cancer cells and tumor-associated macrophages maintains epithelial-mesenchymal transition and endoplasmic reticulum homeostasis in cholangiocarcinoma. Pharmacol. Res. 187 , 106564 (2023). 36423790 10.1016/j.phrs.2022.106564

283. Gerling M Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth Nat. Commun. 2016 7 12321 27492255 10.1038/ncomms12321 PMC4980446 Gerling, M. et al. Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. Nat. Commun. 7 , 12321 (2016). 27492255 10.1038/ncomms12321 PMC4980446

284. Fu X Expression of Indian hedgehog is negatively correlated with APC gene mutation in colorectal tumors Int. J. Clin. Exp. Med. 2014 7 2150 2155 25232400 PMC4161560 Fu, X. et al. Expression of Indian hedgehog is negatively correlated with APC gene mutation in colorectal tumors. Int. J. Clin. Exp. Med. 7 , 2150–2155 (2014). 25232400 PMC4161560

285. Fu X Opposite expression patterns of Sonic hedgehog and Indian hedgehog are associated with aberrant methylation status of their promoters in colorectal cancers Pathology 2010 42 553 559 20854074 10.3109/00313025.2010.508785 Fu, X. et al. Opposite expression patterns of Sonic hedgehog and Indian hedgehog are associated with aberrant methylation status of their promoters in colorectal cancers. Pathology 42 , 553–559 (2010). 20854074 10.3109/00313025.2010.508785

286. Büller N Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice Gastroenterology 2015 148 170 180.e176 25307863 10.1053/j.gastro.2014.10.006 Büller, N. et al. Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice. Gastroenterology 148 , 170–180.e176 (2015). 25307863 10.1053/j.gastro.2014.10.006

287. Tang YA Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer Proc. Natl Acad. Sci. USA 2018 115 E5990 E5999 29891662 10.1073/pnas.1801348115 PMC6042102 Tang, Y. A. et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer. Proc. Natl Acad. Sci. USA 115 , E5990–E5999 (2018). 29891662 10.1073/pnas.1801348115 PMC6042102

288. Klein A Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors Nat. Rev. Gastroenterol. Hepatol. 2021 18 493 502 34002083 10.1038/s41575-021-00457-x PMC9265847 Klein, A. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat. Rev. Gastroenterol. Hepatol. 18 , 493–502 (2021). 34002083 10.1038/s41575-021-00457-x PMC9265847

289. Thayer S Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis Nature 2003 425 851 856 14520413 10.1038/nature02009 PMC3688051 Thayer, S. et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425 , 851–856 (2003). 14520413 10.1038/nature02009 PMC3688051

290. Maréchal R Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma Clin. Cancer Res. 2015 21 1215 1224 25552484 10.1158/1078-0432.CCR-14-0667 Maréchal, R. et al. Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. Clin. Cancer Res. 21 , 1215–1224 (2015). 25552484 10.1158/1078-0432.CCR-14-0667

291. Walter K Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts Clin. Cancer Res. 2010 16 1781 1789 20215540 10.1158/1078-0432.CCR-09-1913 PMC2846609 Walter, K. et al. Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. Clin. Cancer Res. 16 , 1781–1789 (2010). 20215540 10.1158/1078-0432.CCR-09-1913 PMC2846609

292. Inaguma S Kasai K Ikeda H GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin Oncogene 2011 30 714 723 20972463 10.1038/onc.2010.459 Inaguma, S., Kasai, K. & Ikeda, H. GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin. Oncogene 30 , 714–723 (2011). 20972463 10.1038/onc.2010.459

293. Xu X Sonic hedgehog-Gli1 signaling pathway regulates the epithelial mesenchymal transition (EMT) by mediating a new target gene, S100A4, in pancreatic cancer cells PloS One 2014 9 e96441 25072505 10.1371/journal.pone.0096441 PMC4114558 Xu, X. et al. Sonic hedgehog-Gli1 signaling pathway regulates the epithelial mesenchymal transition (EMT) by mediating a new target gene, S100A4, in pancreatic cancer cells. PloS One 9 , e96441 (2014). 25072505 10.1371/journal.pone.0096441 PMC4114558

294. Lee J Stromal response to Hedgehog signaling restrains pancreatic cancer progression Proc. Natl Acad. Sci. USA 2014 111 E3091 E3100 25024225 10.1073/pnas.1411679111 PMC4121834 Lee, J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111 , E3091–E3100 (2014). 25024225 10.1073/pnas.1411679111 PMC4121834

295. Yang Y Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer World J. Gastroenterol. 2017 23 7232 7241 29142470 10.3748/wjg.v23.i40.7232 PMC5677195 Yang, Y. et al. Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer. World J. Gastroenterol. 23 , 7232–7241 (2017). 29142470 10.3748/wjg.v23.i40.7232 PMC5677195

296. Bapat A Hostetter G Von Hoff D Han H Perineural invasion and associated pain in pancreatic cancer Nat. Rev. Cancer 2011 11 695 707 21941281 10.1038/nrc3131 Bapat, A., Hostetter, G., Von Hoff, D. & Han, H. Perineural invasion and associated pain in pancreatic cancer. Nat. Rev. Cancer 11 , 695–707 (2011). 21941281 10.1038/nrc3131

297. Li X Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer Clin. Cancer Res. 2014 20 4326 4338 24947933 10.1158/1078-0432.CCR-13-3426 Li, X. et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20 , 4326–4338 (2014). 24947933 10.1158/1078-0432.CCR-13-3426

298. Ma C Molecular mechanisms involving the sonic hedgehog pathway in lung cancer therapy: recent advances Front. Oncol. 2022 12 729088 35433472 10.3389/fonc.2022.729088 PMC9010822 Ma, C. et al. Molecular mechanisms involving the sonic hedgehog pathway in lung cancer therapy: recent advances. Front. Oncol. 12 , 729088 (2022). 35433472 10.3389/fonc.2022.729088 PMC9010822

299. Bermudez O Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation PloS One 2013 8 e63226 23667589 10.1371/journal.pone.0063226 PMC3646741 Bermudez, O. et al. Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation. PloS One 8 , e63226 (2013). 23667589 10.1371/journal.pone.0063226 PMC3646741

300. Li H Gli promotes epithelial-mesenchymal transition in human lung adenocarcinomas Oncotarget 2016 7 80415 80425 27533453 10.18632/oncotarget.11246 PMC5348330 Li, H. et al. Gli promotes epithelial-mesenchymal transition in human lung adenocarcinomas. Oncotarget 7 , 80415–80425 (2016). 27533453 10.18632/oncotarget.11246 PMC5348330

301. Yue D Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas J. Exp. Clin. Cancer Res. 2014 33 34 24758269 10.1186/1756-9966-33-34 PMC4029998 Yue, D. et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J. Exp. Clin. Cancer Res. 33 , 34 (2014). 24758269 10.1186/1756-9966-33-34 PMC4029998

302. Bai X Blockade of hedgehog signaling synergistically increases sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer cell lines PloS One 2016 11 e0149370 26943330 10.1371/journal.pone.0149370 PMC4778934 Bai, X. et al. Blockade of hedgehog signaling synergistically increases sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer cell lines. PloS One 11 , e0149370 (2016). 26943330 10.1371/journal.pone.0149370 PMC4778934

303. Lin E Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma Oncotarget 2016 7 24179 24193 27015549 10.18632/oncotarget.8253 PMC5029693 Lin, E. et al. Hedgehog pathway maintains cell survival under stress conditions, and drives drug resistance in lung adenocarcinoma. Oncotarget 7 , 24179–24193 (2016). 27015549 10.18632/oncotarget.8253 PMC5029693

304. Seidl C MicroRNA-182-5p regulates hedgehog signaling pathway and chemosensitivity of cisplatin-resistant lung adenocarcinoma cells via targeting GLI2 Cancer Lett. 2020 469 266 276 31697978 10.1016/j.canlet.2019.10.044 Seidl, C. et al. MicroRNA-182-5p regulates hedgehog signaling pathway and chemosensitivity of cisplatin-resistant lung adenocarcinoma cells via targeting GLI2. Cancer Lett. 469 , 266–276 (2020). 31697978 10.1016/j.canlet.2019.10.044

305. Giroux Leprieur E Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer Oncotarget 2017 8 103744 103757 29262597 10.18632/oncotarget.21781 PMC5732763 Giroux Leprieur, E. et al. Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer. Oncotarget 8 , 103744–103757 (2017). 29262597 10.18632/oncotarget.21781 PMC5732763

306. de Cássia Viu Carrara R Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls Clin. Transl. Oncol. 2018 20 542 549 28905209 10.1007/s12094-017-1751-x de Cássia Viu Carrara, R. et al. Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls. Clin. Transl. Oncol. 20 , 542–549 (2018). 28905209 10.1007/s12094-017-1751-x

307. Long B Activation of the Hedgehog pathway in chronic myelogeneous leukemia patients J. Exp. Clin. Cancer Res. 2011 30 8 21235817 10.1186/1756-9966-30-8 PMC3032744 Long, B. et al. Activation of the Hedgehog pathway in chronic myelogeneous leukemia patients. J. Exp. Clin. Cancer Res. 30 , 8 (2011). 21235817 10.1186/1756-9966-30-8 PMC3032744

308. Babashah S Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34 + CML stem/progenitor cells Int. J. Cancer 2013 133 579 589 23341351 10.1002/ijc.28043 Babashah, S. et al. Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34 + CML stem/progenitor cells. Int. J. Cancer 133 , 579–589 (2013). 23341351 10.1002/ijc.28043

309. Dierks C Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation Cancer Cell 2008 14 238 249 18772113 10.1016/j.ccr.2008.08.003 Dierks, C. et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14 , 238–249 (2008). 18772113 10.1016/j.ccr.2008.08.003

310. Sadarangani A GLI2 inhibition abrogates human leukemia stem cell dormancy J. Transl. Med. 2015 13 98 25889765 10.1186/s12967-015-0453-9 PMC4414375 Sadarangani, A. et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J. Transl. Med. 13 , 98 (2015). 25889765 10.1186/s12967-015-0453-9 PMC4414375

311. Wellbrock J Expression of hedgehog pathway mediator GLI represents a negative prognostic marker in human acute myeloid leukemia and its inhibition exerts antileukemic effects Clin. Cancer Res. 2015 21 2388 2398 25745035 10.1158/1078-0432.CCR-14-1059 Wellbrock, J. et al. Expression of hedgehog pathway mediator GLI represents a negative prognostic marker in human acute myeloid leukemia and its inhibition exerts antileukemic effects. Clin. Cancer Res. 21 , 2388–2398 (2015). 25745035 10.1158/1078-0432.CCR-14-1059

312. Lau B Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity Oncogene 2019 38 687 698 30171262 10.1038/s41388-018-0431-9 PMC6358463 Lau, B. et al. Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity. Oncogene 38 , 687–698 (2019). 30171262 10.1038/s41388-018-0431-9 PMC6358463

313. Kobune M Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms Blood Cancer J. 2012 2 e87 22961059 10.1038/bcj.2012.36 PMC3461706 Kobune, M. et al. Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms. Blood Cancer J. 2 , e87 (2012). 22961059 10.1038/bcj.2012.36 PMC3461706

314. Li X Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells Oncotarget 2016 7 33004 33015 27105509 10.18632/oncotarget.8844 PMC5078070 Li, X. et al. Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells. Oncotarget 7 , 33004–33015 (2016). 27105509 10.18632/oncotarget.8844 PMC5078070

315. Hegde G Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target Mol. Cancer Res. 2008 6 1928 1936 19074837 10.1158/1541-7786.MCR-08-0142 Hegde, G. et al. Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol. Cancer Res. 6 , 1928–1936 (2008). 19074837 10.1158/1541-7786.MCR-08-0142

316. Dagklis A Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors Blood 2016 128 2642 2654 27694322 10.1182/blood-2016-03-703454 Dagklis, A. et al. Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors. Blood 128 , 2642–2654 (2016). 27694322 10.1182/blood-2016-03-703454

317. Peacock C Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma Proc. Natl Acad. Sci. USA 2007 104 4048 4053 17360475 10.1073/pnas.0611682104 PMC1805487 Peacock, C. et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl Acad. Sci. USA 104 , 4048–4053 (2007). 17360475 10.1073/pnas.0611682104 PMC1805487

318. Ghia E Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia Blood 2019 133 2651 2663 30923040 10.1182/blood-2018-09-873695 PMC6587306 Ghia, E. et al. Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia. Blood 133 , 2651–2663 (2019). 30923040 10.1182/blood-2018-09-873695 PMC6587306

319. Fagin J Wells S Biologic and clinical perspectives on thyroid cancer N. Engl. J. Med. 2016 375 1054 1067 27626519 10.1056/NEJMra1501993 PMC5512163 Fagin, J. & Wells, S. Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375 , 1054–1067 (2016). 27626519 10.1056/NEJMra1501993 PMC5512163

320. Xu X Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation Endocr. Relat. Cancer 2012 19 167 179 22241722 10.1530/ERC-11-0305 Xu, X. et al. Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation. Endocr. Relat. Cancer 19 , 167–179 (2012). 22241722 10.1530/ERC-11-0305

321. Williamson A The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met Oncotarget 2016 7 10472 10485 26859575 10.18632/oncotarget.7228 PMC4891133 Williamson, A. et al. The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met. Oncotarget 7 , 10472–10485 (2016). 26859575 10.18632/oncotarget.7228 PMC4891133

322. Bian X Expression and clinical significance of Shh/Gli-1 in papillary thyroid carcinoma Tumour Biol. 2014 35 10523 10528 25060182 10.1007/s13277-014-2365-3 Bian, X. et al. Expression and clinical significance of Shh/Gli-1 in papillary thyroid carcinoma. Tumour Biol. 35 , 10523–10528 (2014). 25060182 10.1007/s13277-014-2365-3

323. Lee J GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers Med. (Baltim.) 2015 94 e998 10.1097/MD.0000000000000998 PMC4504527 26107686 Lee, J. et al. GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers. Med. (Baltim.) 94 , e998 (2015). 10.1097/MD.0000000000000998 PMC4504527 26107686

324. Heiden K The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression J. Clin. Endocrinol. Metab. 2014 99 E2178 E2187 25078145 10.1210/jc.2014-1844 PMC5393503 Heiden, K. et al. The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression. J. Clin. Endocrinol. Metab. 99 , E2178–E2187 (2014). 25078145 10.1210/jc.2014-1844 PMC5393503

325. Ma C Ma X Li Y Fu S The role of primary cilia in thyroid cancer: from basic research to clinical applications Front. Endocrinol. (Lausanne) 2021 12 685228 34168619 10.3389/fendo.2021.685228 PMC8218906 Ma, C., Ma, X., Li, Y. & Fu, S. The role of primary cilia in thyroid cancer: from basic research to clinical applications. Front. Endocrinol. (Lausanne) 12 , 685228 (2021). 34168619 10.3389/fendo.2021.685228 PMC8218906

326. Rubin A Chen E Ratner D Basal-cell carcinoma N. Engl. J. Med. 2005 353 2262 2269 16306523 10.1056/NEJMra044151 Rubin, A., Chen, E. & Ratner, D. Basal-cell carcinoma. N. Engl. J. Med. 353 , 2262–2269 (2005). 16306523 10.1056/NEJMra044151

327. Xie J Activating smoothened mutations in sporadic basal-cell carcinoma Nature 1998 391 90 92 9422511 10.1038/34201 Xie, J. et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 391 , 90–92 (1998). 9422511 10.1038/34201

328. Gailani M The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas Nat. Genet. 1996 14 78 81 8782823 10.1038/ng0996-78 Gailani, M. et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat. Genet. 14 , 78–81 (1996). 8782823 10.1038/ng0996-78

329. Deng L Expression of hedgehog signaling pathway proteins in basal cell carcinoma: clinicopathologic study Clin. Cosmet. Investig. Dermatol. 2022 15 2353 2361 36348957 10.2147/CCID.S389551 PMC9637365 Deng, L. et al. Expression of hedgehog signaling pathway proteins in basal cell carcinoma: clinicopathologic study. Clin. Cosmet. Investig. Dermatol. 15 , 2353–2361 (2022). 36348957 10.2147/CCID.S389551 PMC9637365

330. Moisejenko-Golubovica J Volkov O Ivanova A Groma V Analysis of the occurrence and distribution of primary and recurrent basal cell carcinoma of head and neck coupled to the assessment of tumor microenvironment and Sonic hedgehog signaling Rom. J. Morphol. Embryol. 2020 61 821 831 33817723 10.47162/RJME.61.3.20 PMC8112792 Moisejenko-Golubovica, J., Volkov, O., Ivanova, A. & Groma, V. Analysis of the occurrence and distribution of primary and recurrent basal cell carcinoma of head and neck coupled to the assessment of tumor microenvironment and Sonic hedgehog signaling. Rom. J. Morphol. Embryol. 61 , 821–831 (2020). 33817723 10.47162/RJME.61.3.20 PMC8112792

331. Kim H Expression profile of sonic hedgehog signaling-related molecules in basal cell carcinoma PloS One 2019 14 e0225511 31756206 10.1371/journal.pone.0225511 PMC6874381 Kim, H. et al. Expression profile of sonic hedgehog signaling-related molecules in basal cell carcinoma. PloS One 14 , e0225511 (2019). 31756206 10.1371/journal.pone.0225511 PMC6874381

332. Sánchez-Danés A Defining the clonal dynamics leading to mouse skin tumour initiation Nature 2016 536 298 303 27459053 10.1038/nature19069 PMC5068560 Sánchez-Danés, A. et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536 , 298–303 (2016). 27459053 10.1038/nature19069 PMC5068560

333. Kuonen F Loss of primary cilia drives switching from hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma J. Invest. Dermatol. 2019 139 1439 1448 30707899 10.1016/j.jid.2018.11.035 PMC6591089 Kuonen, F. et al. Loss of primary cilia drives switching from hedgehog to Ras/MAPK pathway in resistant basal cell carcinoma. J. Invest. Dermatol. 139 , 1439–1448 (2019). 30707899 10.1016/j.jid.2018.11.035 PMC6591089

334. Jacquet A Dormoy V Lorenzato M Durlach A Preliminary results on a proposed histopathological assessment of predictive factors for basal cell carcinoma recurrence after primary free margin excision Ski. Health Dis. 2022 2 e88 10.1002/ski2.88 PMC9168020 35677922 Jacquet, A., Dormoy, V., Lorenzato, M. & Durlach, A. Preliminary results on a proposed histopathological assessment of predictive factors for basal cell carcinoma recurrence after primary free margin excision. Ski. Health Dis. 2 , e88 (2022). 10.1002/ski2.88 PMC9168020 35677922

335. Whitson R Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas Nat. Med. 2018 24 271 281 29400712 10.1038/nm.4476 PMC5839965 Whitson, R. et al. Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nat. Med. 24 , 271–281 (2018). 29400712 10.1038/nm.4476 PMC5839965

336. Riobo-Del Galdo NA Lara Montero Á Wertheimer EV Role of hedgehog signaling in breast cancer: pathogenesis and therapeutics Cells 2019 8 375 31027259 10.3390/cells8040375 PMC6523618 Riobo-Del Galdo, N. A., Lara Montero, Á. & Wertheimer, E. V. Role of hedgehog signaling in breast cancer: pathogenesis and therapeutics. Cells 8 , 375 (2019). 31027259 10.3390/cells8040375 PMC6523618

337. McDermott KM Liu BY Tlsty TD Pazour GJ Primary cilia regulate branching morphogenesis during mammary gland development Curr. Biol. 2010 20 731 737 20381354 10.1016/j.cub.2010.02.048 PMC2916967 McDermott, K. M., Liu, B. Y., Tlsty, T. D. & Pazour, G. J. Primary cilia regulate branching morphogenesis during mammary gland development. Curr. Biol. 20 , 731–737 (2010). 20381354 10.1016/j.cub.2010.02.048 PMC2916967

338. Qayoom H Wani NA Alshehri B Mir MA An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer Future Oncol. 2021 17 4185 4206 34342489 10.2217/fon-2021-0172 Qayoom, H., Wani, N. A., Alshehri, B. & Mir, M. A. An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol. 17 , 4185–4206 (2021). 34342489 10.2217/fon-2021-0172

339. Bhateja P Cherian M Majumder S Ramaswamy B The hedgehog signaling pathway: a viable target in breast cancer? Cancers (Basel) 2019 11 1126 31394751 10.3390/cancers11081126 PMC6721501 Bhateja, P., Cherian, M., Majumder, S. & Ramaswamy, B. The hedgehog signaling pathway: a viable target in breast cancer? Cancers (Basel) 11 , 1126 (2019). 31394751 10.3390/cancers11081126 PMC6721501

340. Riaz SK Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer Cell Commun. Signal 2018 16 3 29329585 10.1186/s12964-017-0213-y PMC5795292 Riaz, S. K. et al. Involvement of hedgehog pathway in early onset, aggressive molecular subtypes and metastatic potential of breast cancer. Cell Commun. Signal 16 , 3 (2018). 29329585 10.1186/s12964-017-0213-y PMC5795292

341. Tao Y Mao J Zhang Q Li L Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer Oncol. Lett. 2011 2 995 1001 22866163 10.3892/ol.2011.357 PMC3408022 Tao, Y., Mao, J., Zhang, Q. & Li, L. Overexpression of Hedgehog signaling molecules and its involvement in triple-negative breast cancer. Oncol. Lett. 2 , 995–1001 (2011). 22866163 10.3892/ol.2011.357 PMC3408022

342. Noman AS Overexpression of sonic hedgehog in the triple negative breast cancer: clinicopathological characteristics of high burden breast cancer patients from Bangladesh Sci. Rep. 2016 6 18830 26727947 10.1038/srep18830 PMC4700415 Noman, A. S. et al. Overexpression of sonic hedgehog in the triple negative breast cancer: clinicopathological characteristics of high burden breast cancer patients from Bangladesh. Sci. Rep. 6 , 18830 (2016). 26727947 10.1038/srep18830 PMC4700415

343. Di Mauro C Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers Br. J. Cancer 2017 116 1425 1435 28441382 10.1038/bjc.2017.116 PMC5520095 Di Mauro, C. et al. Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers. Br. J. Cancer 116 , 1425–1435 (2017). 28441382 10.1038/bjc.2017.116 PMC5520095

344. Reyes-Ramos AM Mesenchymal cells support the oncogenicity and therapeutic response of the hedgehog pathway in triple-negative breast cancer Cancers (Basel) 2019 11 1522 31658643 10.3390/cancers11101522 PMC6826628 Reyes-Ramos, A. M. et al. Mesenchymal cells support the oncogenicity and therapeutic response of the hedgehog pathway in triple-negative breast cancer. Cancers (Basel) 11 , 1522 (2019). 31658643 10.3390/cancers11101522 PMC6826628

345. Cazet A Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer Nat. Commun. 2018 9 2897 30042390 10.1038/s41467-018-05220-6 PMC6057940 Cazet, A. et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat. Commun. 9 , 2897 (2018). 30042390 10.1038/s41467-018-05220-6 PMC6057940

346. Sims-Mourtada J Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy Mol. Carcinog. 2015 54 1480 1493 25263583 10.1002/mc.22225 Sims-Mourtada, J. et al. Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy. Mol. Carcinog. 54 , 1480–1493 (2015). 25263583 10.1002/mc.22225

347. Zarzosa P Targeting the Hedgehog pathway in rhabdomyosarcoma Cancers (Basel) 2023 15 727 36765685 10.3390/cancers15030727 PMC9913695 Zarzosa, P. et al. Targeting the Hedgehog pathway in rhabdomyosarcoma. Cancers (Basel) 15 , 727 (2023). 36765685 10.3390/cancers15030727 PMC9913695

348. Belyea B Embryonic signaling pathways and rhabdomyosarcoma: contributions to cancer development and opportunities for therapeutic targeting Sarcoma 2012 2012 406239 22619564 10.1155/2012/406239 PMC3350847 Belyea, B. et al. Embryonic signaling pathways and rhabdomyosarcoma: contributions to cancer development and opportunities for therapeutic targeting. Sarcoma 2012 , 406239 (2012). 22619564 10.1155/2012/406239 PMC3350847

349. Hahn H Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome Nat. Med. 1998 4 619 622 9585239 10.1038/nm0598-619 Hahn, H. et al. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat. Med. 4 , 619–622 (1998). 9585239 10.1038/nm0598-619

350. Teot L Clinical and mutational spectrum of highly differentiated, paired box 3:forkhead box protein o1 fusion-negative rhabdomyosarcoma: a report from the Children’s Oncology Group Cancer 2018 124 1973 1981 29461635 10.1002/cncr.31286 PMC5910184 Teot, L. et al. Clinical and mutational spectrum of highly differentiated, paired box 3:forkhead box protein o1 fusion-negative rhabdomyosarcoma: a report from the Children’s Oncology Group. Cancer 124 , 1973–1981 (2018). 29461635 10.1002/cncr.31286 PMC5910184

351. Tostar U Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development J. Pathol. 2006 208 17 25 16294371 10.1002/path.1882 Tostar, U. et al. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J. Pathol. 208 , 17–25 (2006). 16294371 10.1002/path.1882

352. Almazán-Moga A Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands Br. J. Cancer 2017 117 1314 1325 28881358 10.1038/bjc.2017.305 PMC5672936 Almazán-Moga, A. et al. Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands. Br. J. Cancer 117 , 1314–1325 (2017). 28881358 10.1038/bjc.2017.305 PMC5672936

353. Hatley ME A mouse model of rhabdomyosarcoma originating from the adipocyte lineage Cancer Cell 2012 22 536 546 23079662 10.1016/j.ccr.2012.09.004 PMC3479681 Hatley, M. E. et al. A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 22 , 536–546 (2012). 23079662 10.1016/j.ccr.2012.09.004 PMC3479681

354. Fu W Asp P Canter B Dynlacht BD Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma Proc. Natl Acad. Sci. USA 2014 111 9151 9156 24927541 10.1073/pnas.1323265111 PMC4078804 Fu, W., Asp, P., Canter, B. & Dynlacht, B. D. Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma. Proc. Natl Acad. Sci. USA 111 , 9151–9156 (2014). 24927541 10.1073/pnas.1323265111 PMC4078804

355. Ridzewski R Hedgehog inhibitors in Rhabdomyosarcoma: a comparison of four compounds and responsiveness of four cell lines Front. Oncol. 2015 5 130 26106586 10.3389/fonc.2015.00130 PMC4459089 Ridzewski, R. et al. Hedgehog inhibitors in Rhabdomyosarcoma: a comparison of four compounds and responsiveness of four cell lines. Front. Oncol. 5 , 130 (2015). 26106586 10.3389/fonc.2015.00130 PMC4459089

356. Satheesha S Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma Oncogene 2016 35 2020 2030 26189795 10.1038/onc.2015.267 PMC5399168 Satheesha, S. et al. Targeting hedgehog signaling reduces self-renewal in embryonal rhabdomyosarcoma. Oncogene 35 , 2020–2030 (2016). 26189795 10.1038/onc.2015.267 PMC5399168

357. Yoon JW Up-regulation of GLI1 in vincristine-resistant rhabdomyosarcoma and Ewing sarcoma BMC Cancer 2020 20 511 32493277 10.1186/s12885-020-06985-0 PMC7310145 Yoon, J. W. et al. Up-regulation of GLI1 in vincristine-resistant rhabdomyosarcoma and Ewing sarcoma. BMC Cancer 20 , 511 (2020). 32493277 10.1186/s12885-020-06985-0 PMC7310145

358. Patel TH Cecchini M Targeted therapies in advanced gastric cancer Curr. Treat. Options Oncol. 2020 21 70 32725377 10.1007/s11864-020-00774-4 Patel, T. H. & Cecchini, M. Targeted therapies in advanced gastric cancer. Curr. Treat. Options Oncol. 21 , 70 (2020). 32725377 10.1007/s11864-020-00774-4

359. Xu Y Song S Wang Z Ajani JA The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective Cell Commun. Signal 2019 17 157 31775795 10.1186/s12964-019-0479-3 PMC6882007 Xu, Y., Song, S., Wang, Z. & Ajani, J. A. The role of hedgehog signaling in gastric cancer: molecular mechanisms, clinical potential, and perspective. Cell Commun. Signal 17 , 157 (2019). 31775795 10.1186/s12964-019-0479-3 PMC6882007

360. Wessler S Krisch LM Elmer DP Aberger F From inflammation to gastric cancer - the importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases Cell Commun. Signal 2017 15 15 28427431 10.1186/s12964-017-0171-4 PMC5397778 Wessler, S., Krisch, L. M., Elmer, D. P. & Aberger, F. From inflammation to gastric cancer - the importance of Hedgehog/GLI signaling in Helicobacter pylori-induced chronic inflammatory and neoplastic diseases. Cell Commun. Signal 15 , 15 (2017). 28427431 10.1186/s12964-017-0171-4 PMC5397778

361. Akyala AI Peppelenbosch MP Gastric cancer and Hedgehog signaling pathway: emerging new paradigms Genes Cancer 2018 9 1 10 29725500 10.18632/genesandcancer.168 PMC5931255 Akyala, A. I. & Peppelenbosch, M. P. Gastric cancer and Hedgehog signaling pathway: emerging new paradigms. Genes Cancer 9 , 1–10 (2018). 29725500 10.18632/genesandcancer.168 PMC5931255

362. Shiotani A Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression Aliment Pharmacol. Ther. 2006 24 71 80 17209848 10.1111/j.1365-2036.2006.00028.x Shiotani, A. et al. Helicobacter pylori-induced atrophic gastritis progressing to gastric cancer exhibits sonic hedgehog loss and aberrant CDX2 expression. Aliment Pharmacol. Ther. 24 , 71–80 (2006). 17209848 10.1111/j.1365-2036.2006.00028.x

363. Schumacher MA Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori Gastroenterology 2012 142 1150 1159.e1156 22285806 10.1053/j.gastro.2012.01.029 PMC3335966 Schumacher, M. A. et al. Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori. Gastroenterology 142 , 1150–1159.e1156 (2012). 22285806 10.1053/j.gastro.2012.01.029 PMC3335966

364. Akhtar K Role of sonic hedgehog ligand in gastric cancer therapeutics J. Cancer Res. Ther. 2022 18 S267 S272 36510975 10.4103/jcrt.jcrt_739_21 Akhtar, K. et al. Role of sonic hedgehog ligand in gastric cancer therapeutics. J. Cancer Res. Ther. 18 , S267–S272 (2022). 36510975 10.4103/jcrt.jcrt_739_21

365. Shiotani A Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer Am. J. Gastroenterol. 2005 100 581 587 15743355 10.1111/j.1572-0241.2005.41001.x Shiotani, A. et al. Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer. Am. J. Gastroenterol. 100 , 581–587 (2005). 15743355 10.1111/j.1572-0241.2005.41001.x

366. Lu L Prognostic and clinicopathological value of Gli-1 expression in gastric cancer: a meta-analysis Oncotarget 2016 7 69087 69096 27634907 10.18632/oncotarget.12011 PMC5356614 Lu, L. et al. Prognostic and clinicopathological value of Gli-1 expression in gastric cancer: a meta-analysis. Oncotarget 7 , 69087–69096 (2016). 27634907 10.18632/oncotarget.12011 PMC5356614

367. Yu B The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer J. Genet. Genomics 2017 44 375 383 28847472 10.1016/j.jgg.2017.04.008 PMC5604254 Yu, B. et al. The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer. J. Genet. Genomics 44 , 375–383 (2017). 28847472 10.1016/j.jgg.2017.04.008 PMC5604254

368. Xu M Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44(+)/Musashi-1(+) gastric cancer stem cells Cancer Lett. 2015 369 124 133 26276718 10.1016/j.canlet.2015.08.005 Xu, M. et al. Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44(+)/Musashi-1(+) gastric cancer stem cells. Cancer Lett. 369 , 124–133 (2015). 26276718 10.1016/j.canlet.2015.08.005

369. Yoon C CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance Clin. Cancer Res. 2014 20 3974 3988 24947926 10.1158/1078-0432.CCR-14-0011 PMC4135312 Yoon, C. et al. CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin. Cancer Res. 20 , 3974–3988 (2014). 24947926 10.1158/1078-0432.CCR-14-0011 PMC4135312

370. Koh V Hedgehog transcriptional effector GLI mediates mTOR-Induced PD-L1 expression in gastric cancer organoids Cancer Lett. 2021 518 59 71 34126195 10.1016/j.canlet.2021.06.007 PMC8606306 Koh, V. et al. Hedgehog transcriptional effector GLI mediates mTOR-Induced PD-L1 expression in gastric cancer organoids. Cancer Lett. 518 , 59–71 (2021). 34126195 10.1016/j.canlet.2021.06.007 PMC8606306

371. Wu C Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy Onco Targets Ther. 2017 10 3249 3259 28721076 10.2147/OTT.S139639 PMC5501640 Wu, C. et al. Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy. Onco Targets Ther. 10 , 3249–3259 (2017). 28721076 10.2147/OTT.S139639 PMC5501640

372. Gu D Schlotman K Xie J Deciphering the role of hedgehog signaling in pancreatic cancer J. Biomed. Res. 2016 30 353 360 27346466 10.7555/JBR.30.20150107 PMC5044707 Gu, D., Schlotman, K. & Xie, J. Deciphering the role of hedgehog signaling in pancreatic cancer. J. Biomed. Res. 30 , 353–360 (2016). 27346466 10.7555/JBR.30.20150107 PMC5044707

373. Cohen M Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene Oncologist 2001 6 4 11 11161223 10.1634/theoncologist.6-1-4 Cohen, M. et al. Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene. Oncologist 6 , 4–11 (2001). 11161223 10.1634/theoncologist.6-1-4

374. Axelson M U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma Clin. Cancer Res. 2013 19 2289 2293 23515405 10.1158/1078-0432.CCR-12-1956 Axelson, M. et al. U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin. Cancer Res. 19 , 2289–2293 (2013). 23515405 10.1158/1078-0432.CCR-12-1956

375. Burness C Sonidegib: first global approval Drugs 2015 75 1559 1566 26323341 10.1007/s40265-015-0458-y Burness, C. Sonidegib: first global approval. Drugs 75 , 1559–1566 (2015). 26323341 10.1007/s40265-015-0458-y

376. Hoy S Glasdegib: first global approval Drugs 2019 79 207 213 30666593 10.1007/s40265-018-1047-7 Hoy, S. Glasdegib: first global approval. Drugs 79 , 207–213 (2019). 30666593 10.1007/s40265-018-1047-7

377. Metcalfe C de Sauvage F Hedgehog fights back: mechanisms of acquired resistance against smoothened antagonists Cancer Res. 2011 71 5057 5061 21771911 10.1158/0008-5472.CAN-11-0923 Metcalfe, C. & de Sauvage, F. Hedgehog fights back: mechanisms of acquired resistance against smoothened antagonists. Cancer Res. 71 , 5057–5061 (2011). 21771911 10.1158/0008-5472.CAN-11-0923

378. Wang C Structural basis for smoothened receptor modulation and chemoresistance to anticancer drugs Nat. Commun. 2014 5 4355 25008467 10.1038/ncomms5355 PMC4198951 Wang, C. et al. Structural basis for smoothened receptor modulation and chemoresistance to anticancer drugs. Nat. Commun. 5 , 4355 (2014). 25008467 10.1038/ncomms5355 PMC4198951

379. Tu J Molecular modeling study on resistance of WT/D473H SMO to antagonists LDE-225 and LEQ-506 Pharmacol. Res. 2018 129 491 499 29175550 10.1016/j.phrs.2017.11.025 Tu, J. et al. Molecular modeling study on resistance of WT/D473H SMO to antagonists LDE-225 and LEQ-506. Pharmacol. Res. 129 , 491–499 (2018). 29175550 10.1016/j.phrs.2017.11.025

380. Ishii T Inhibition mechanism exploration of investigational drug TAK-441 as inhibitor against vismodegib-resistant smoothened mutant Eur. J. Pharmacol. 2014 723 305 313 24291104 10.1016/j.ejphar.2013.11.014 Ishii, T. et al. Inhibition mechanism exploration of investigational drug TAK-441 as inhibitor against vismodegib-resistant smoothened mutant. Eur. J. Pharmacol. 723 , 305–313 (2014). 24291104 10.1016/j.ejphar.2013.11.014

381. Coupland C Structure, mechanism, and inhibition of Hedgehog acyltransferase Mol. Cell 2021 81 5025 5038.e5010 34890564 10.1016/j.molcel.2021.11.018 PMC8693861 Coupland, C. et al. Structure, mechanism, and inhibition of Hedgehog acyltransferase. Mol. Cell 81 , 5025–5038.e5010 (2021). 34890564 10.1016/j.molcel.2021.11.018 PMC8693861

382. Petrova E Inhibitors of hedgehog acyltransferase block sonic hedgehog signaling Nat. Chem. Biol. 2013 9 247 249 23416332 10.1038/nchembio.1184 PMC3604071 Petrova, E. et al. Inhibitors of hedgehog acyltransferase block sonic hedgehog signaling. Nat. Chem. Biol. 9 , 247–249 (2013). 23416332 10.1038/nchembio.1184 PMC3604071

383. Petrova E Matevossian A Resh M Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma Oncogene 2015 34 263 268 24469057 10.1038/onc.2013.575 PMC4513646 Petrova, E., Matevossian, A. & Resh, M. Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma. Oncogene 34 , 263–268 (2015). 24469057 10.1038/onc.2013.575 PMC4513646

384. Matevossian A Resh M Hedgehog acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells Mol. Cancer 2015 14 72 25889650 10.1186/s12943-015-0345-x PMC4711017 Matevossian, A. & Resh, M. Hedgehog acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells. Mol. Cancer 14 , 72 (2015). 25889650 10.1186/s12943-015-0345-x PMC4711017

385. Andrei S Tate E Lanyon-Hogg T Evaluating hedgehog acyltransferase activity and inhibition using the acylation-coupled lipophilic induction of polarization (Acyl-cLIP) assay Methods Mol. Biol. 2022 2374 13 26 34562239 10.1007/978-1-0716-1701-4_2 Andrei, S., Tate, E. & Lanyon-Hogg, T. Evaluating hedgehog acyltransferase activity and inhibition using the acylation-coupled lipophilic induction of polarization (Acyl-cLIP) assay. Methods Mol. Biol. 2374 , 13–26 (2022). 34562239 10.1007/978-1-0716-1701-4_2

386. Lanyon-Hogg T Photochemical probe identification of a small-molecule inhibitor binding site in hedgehog acyltransferase (HHAT)* Angew. Chem. Int. Ed. Engl. 2021 60 13542 13547 33768725 10.1002/anie.202014457 PMC8252026 Lanyon-Hogg, T. et al. Photochemical probe identification of a small-molecule inhibitor binding site in hedgehog acyltransferase (HHAT)*. Angew. Chem. Int. Ed. Engl. 60 , 13542–13547 (2021). 33768725 10.1002/anie.202014457 PMC8252026

387. Bosanac I The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling Nat. Struct. Mol. Biol. 2009 16 691 697 19561609 10.1038/nsmb.1632 Bosanac, I. et al. The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling. Nat. Struct. Mol. Biol. 16 , 691–697 (2009). 19561609 10.1038/nsmb.1632

388. Magistri P SMO inhibition modulates cellular plasticity and invasiveness in colorectal cancer Front. Pharmacol. 2017 8 956 29456503 10.3389/fphar.2017.00956 PMC5801594 Magistri, P. et al. SMO inhibition modulates cellular plasticity and invasiveness in colorectal cancer. Front. Pharmacol. 8 , 956 (2017). 29456503 10.3389/fphar.2017.00956 PMC5801594

389. Song Z Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer PloS One 2011 6 e17687 21394208 10.1371/journal.pone.0017687 PMC3048871 Song, Z. et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PloS One 6 , e17687 (2011). 21394208 10.1371/journal.pone.0017687 PMC3048871

390. Decker S Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL Blood 2012 119 997 1007 22130798 10.1182/blood-2011-06-359075 Decker, S. et al. Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL. Blood 119 , 997–1007 (2012). 22130798 10.1182/blood-2011-06-359075

391. Griffiths S Hedgehog-interacting protein is a multimodal antagonist of hedgehog signalling Nat. Commun. 2021 12 7171 34887403 10.1038/s41467-021-27475-2 PMC8660895 Griffiths, S. et al. Hedgehog-interacting protein is a multimodal antagonist of hedgehog signalling. Nat. Commun. 12 , 7171 (2021). 34887403 10.1038/s41467-021-27475-2 PMC8660895

392. Tada M Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma Clin. Cancer Res. 2008 14 3768 3776 18559595 10.1158/1078-0432.CCR-07-1181 Tada, M. et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin. Cancer Res. 14 , 3768–3776 (2008). 18559595 10.1158/1078-0432.CCR-07-1181

393. Martin S Aberrant methylation of the human hedgehog interacting protein (HHIP) gene in pancreatic neoplasms Cancer Biol. Ther. 2005 4 728 733 15970691 10.4161/cbt.4.7.1802 Martin, S. et al. Aberrant methylation of the human hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biol. Ther. 4 , 728–733 (2005). 15970691 10.4161/cbt.4.7.1802

394. Shahi M Human hedgehog interacting protein expression and promoter methylation in medulloblastoma cell lines and primary tumor samples J. Neurooncol. 2011 103 287 296 20853133 10.1007/s11060-010-0401-8 PMC4510471 Shahi, M. et al. Human hedgehog interacting protein expression and promoter methylation in medulloblastoma cell lines and primary tumor samples. J. Neurooncol. 103 , 287–296 (2011). 20853133 10.1007/s11060-010-0401-8 PMC4510471

395. Taniguchi H Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer J. Pathol. 2007 213 131 139 17724792 10.1002/path.2216 Taniguchi, H. et al. Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. J. Pathol. 213 , 131–139 (2007). 17724792 10.1002/path.2216

396. Song Y HHIP overexpression suppresses human gastric cancer progression and metastasis by reducing its CpG island methylation Front. Oncol. 2020 10 1667 33415068 10.3389/fonc.2020.01667 PMC7784629 Song, Y. et al. HHIP overexpression suppresses human gastric cancer progression and metastasis by reducing its CpG island methylation. Front. Oncol. 10 , 1667 (2020). 33415068 10.3389/fonc.2020.01667 PMC7784629

397. Stanton B A small molecule that binds hedgehog and blocks its signaling in human cells Nat. Chem. Biol. 2009 5 154 156 19151731 10.1038/nchembio.142 PMC2770933 Stanton, B. et al. A small molecule that binds hedgehog and blocks its signaling in human cells. Nat. Chem. Biol. 5 , 154–156 (2009). 19151731 10.1038/nchembio.142 PMC2770933

398. Taipale J Cooper M Maiti T Beachy P Patched acts catalytically to suppress the activity of smoothened Nature 2002 418 892 897 12192414 10.1038/nature00989 Taipale, J., Cooper, M., Maiti, T. & Beachy, P. Patched acts catalytically to suppress the activity of smoothened. Nature 418 , 892–897 (2002). 12192414 10.1038/nature00989

399. Hasan Ali O Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome J. Eur. Acad. Dermatol. Venereol. 2021 35 396 402 32564428 10.1111/jdv.16767 PMC7750252 Hasan Ali, O. et al. Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome. J. Eur. Acad. Dermatol. Venereol. 35 , 396–402 (2021). 32564428 10.1111/jdv.16767 PMC7750252

400. Banerjee S Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma J. Transl. Med. 2019 17 246 31362756 10.1186/s12967-019-1995-z PMC6668176 Banerjee, S. et al. Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma. J. Transl. Med. 17 , 246 (2019). 31362756 10.1186/s12967-019-1995-z PMC6668176

401. Sur S Tea polyphenols epigallocatechin gallete and theaflavin restrict mouse liver carcinogenesis through modulation of self-renewal Wnt and hedgehog pathways J. Nutr. Biochem. 2016 27 32 42 26386739 10.1016/j.jnutbio.2015.08.016 Sur, S. et al. Tea polyphenols epigallocatechin gallete and theaflavin restrict mouse liver carcinogenesis through modulation of self-renewal Wnt and hedgehog pathways. J. Nutr. Biochem. 27 , 32–42 (2016). 26386739 10.1016/j.jnutbio.2015.08.016

402. Chen J Taipale J Cooper M Beachy P Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened Genes Dev. 2002 16 2743 2748 12414725 10.1101/gad.1025302 PMC187469 Chen, J., Taipale, J., Cooper, M. & Beachy, P. Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 16 , 2743–2748 (2002). 12414725 10.1101/gad.1025302 PMC187469

403. Turner M Cyclopamine bioactivity by extraction method from veratrum californicum Bioorg. Med. Chem. 2016 24 3752 3757 27338657 10.1016/j.bmc.2016.06.017 PMC4955791 Turner, M. et al. Cyclopamine bioactivity by extraction method from veratrum californicum. Bioorg. Med. Chem. 24 , 3752–3757 (2016). 27338657 10.1016/j.bmc.2016.06.017 PMC4955791

404. Cheng W Role of hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells Int. J. Oncol. 2009 34 829 836 19212688 10.3892/ijo_00000209 Cheng, W. et al. Role of hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int. J. Oncol. 34 , 829–836 (2009). 19212688 10.3892/ijo_00000209

405. Chen X Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro Arch. Med. Res. 2010 41 315 323 20851287 10.1016/j.arcmed.2010.06.003 Chen, X. et al. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch. Med. Res. 41 , 315–323 (2010). 20851287 10.1016/j.arcmed.2010.06.003

406. Jeng K Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: an in vivo study Oncol. Lett. 2012 4 1158 1162 23205113 10.3892/ol.2012.935 PMC3506746 Jeng, K. et al. Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: an in vivo study. Oncol. Lett. 4 , 1158–1162 (2012). 23205113 10.3892/ol.2012.935 PMC3506746

407. Miyazaki Y Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition Mol. Cancer 2016 15 49 27349387 10.1186/s12943-016-0534-2 PMC4924257 Miyazaki, Y. et al. Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition. Mol. Cancer 15 , 49 (2016). 27349387 10.1186/s12943-016-0534-2 PMC4924257

408. Balbous A Selective release of a cyclopamine glucuronide prodrug toward stem-like cancer cell inhibition in glioblastoma Mol. Cancer Ther. 2014 13 2159 2169 25053823 10.1158/1535-7163.MCT-13-1038 Balbous, A. et al. Selective release of a cyclopamine glucuronide prodrug toward stem-like cancer cell inhibition in glioblastoma. Mol. Cancer Ther. 13 , 2159–2169 (2014). 25053823 10.1158/1535-7163.MCT-13-1038

409. Lin T Matsui W Hedgehog pathway as a drug target: smoothened inhibitors in development Onco Targets Ther. 2012 5 47 58 22500124 10.2147/OTT.S21957 PMC3325001 Lin, T. & Matsui, W. Hedgehog pathway as a drug target: smoothened inhibitors in development. Onco Targets Ther. 5 , 47–58 (2012). 22500124 10.2147/OTT.S21957 PMC3325001

410. Tsai C Sonic hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma J. Gastroenterol. Hepatol. 2015 30 1317 1324 25682950 10.1111/jgh.12931 Tsai, C. et al. Sonic hedgehog inhibition as a strategy to augment radiosensitivity of hepatocellular carcinoma. J. Gastroenterol. Hepatol. 30 , 1317–1324 (2015). 25682950 10.1111/jgh.12931

411. Robarge K GDC-0449-a potent inhibitor of the hedgehog pathway Bioorg. Med. Chem. Lett. 2009 19 5576 5581 19716296 10.1016/j.bmcl.2009.08.049 Robarge, K. et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 19 , 5576–5581 (2009). 19716296 10.1016/j.bmcl.2009.08.049

412. Sekulic A Efficacy and safety of vismodegib in advanced basal-cell carcinoma N. Engl. J. Med. 2012 366 2171 2179 22670903 10.1056/NEJMoa1113713 PMC5278761 Sekulic, A. et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 366 , 2171–2179 (2012). 22670903 10.1056/NEJMoa1113713 PMC5278761

413. Sekulic A Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study BMC Cancer 2017 17 332 28511673 10.1186/s12885-017-3286-5 PMC5433030 Sekulic, A. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer 17 , 332 (2017). 28511673 10.1186/s12885-017-3286-5 PMC5433030

414. Dréno B Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial Lancet Oncol. 2017 18 404 412 28188086 10.1016/S1470-2045(17)30072-4 Dréno, B. et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, double-blind, phase 2 trial. Lancet Oncol. 18 , 404–412 (2017). 28188086 10.1016/S1470-2045(17)30072-4

415. Gajjar A Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study Clin. Cancer Res. 2013 19 6305 6312 24077351 10.1158/1078-0432.CCR-13-1425 PMC3856244 Gajjar, A. et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a pediatric brain tumor consortium study. Clin. Cancer Res. 19 , 6305–6312 (2013). 24077351 10.1158/1078-0432.CCR-13-1425 PMC3856244

416. Ally M The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome JAMA Dermatol. 2014 150 542 545 24623282 10.1001/jamadermatol.2013.7444 PMC4024084 Ally, M. et al. The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol. 150 , 542–545 (2014). 24623282 10.1001/jamadermatol.2013.7444 PMC4024084

417. Jacobsen AA Hedgehog pathway inhibitor therapy for locally advanced and metastatic basal cell carcinoma: a systematic review and pooled analysis of interventional studies JAMA Dermatol. 2016 152 816 824 27096888 10.1001/jamadermatol.2016.0780 Jacobsen, A. A. et al. Hedgehog pathway inhibitor therapy for locally advanced and metastatic basal cell carcinoma: a systematic review and pooled analysis of interventional studies. JAMA Dermatol. 152 , 816–824 (2016). 27096888 10.1001/jamadermatol.2016.0780

418. Catenacci D Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer J. Clin. Oncol. 2015 33 4284 4292 26527777 10.1200/JCO.2015.62.8719 PMC4678179 Catenacci, D. et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33 , 4284–4292 (2015). 26527777 10.1200/JCO.2015.62.8719 PMC4678179

419. Houot R Inhibition of hedgehog signaling for the treatment of lymphoma and CLL: a phase II study from the LYSA Ann. Oncol. 2016 27 1349 1350 27002105 10.1093/annonc/mdw138 Houot, R. et al. Inhibition of hedgehog signaling for the treatment of lymphoma and CLL: a phase II study from the LYSA. Ann. Oncol. 27 , 1349–1350 (2016). 27002105 10.1093/annonc/mdw138

420. Italiano A GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute single-arm phase II collaborative study Ann. Oncol. 2013 24 2922 2926 24170610 10.1093/annonc/mdt391 PMC3811907 Italiano, A. et al. GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute single-arm phase II collaborative study. Ann. Oncol. 24 , 2922–2926 (2013). 24170610 10.1093/annonc/mdt391 PMC3811907

421. Calzavara Pinton P Vismodegib in the treatment of basal cell carcinoma: indications for clinical practice Future Oncol. 2015 11 1429 1435 25952787 10.2217/fon.15.20 Calzavara Pinton, P. et al. Vismodegib in the treatment of basal cell carcinoma: indications for clinical practice. Future Oncol. 11 , 1429–1435 (2015). 25952787 10.2217/fon.15.20

422. Pan S Discovery of NVP-LDE225, a potent and selective smoothened antagonist ACS Med. Chem. Lett. 2010 1 130 134 24900187 10.1021/ml1000307 PMC4007689 Pan, S. et al. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS Med. Chem. Lett. 1 , 130–134 (2010). 24900187 10.1021/ml1000307 PMC4007689

423. Fu J NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200 Neuro Oncol. 2013 15 691 706 23482671 10.1093/neuonc/not011 PMC3661095 Fu, J. et al. NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro Oncol. 15 , 691–706 (2013). 23482671 10.1093/neuonc/not011 PMC3661095

424. Nanta R NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128 Oncogenesis 2013 2 e42 23567619 10.1038/oncsis.2013.5 PMC3641359 Nanta, R. et al. NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128. Oncogenesis 2 , e42 (2013). 23567619 10.1038/oncsis.2013.5 PMC3641359

425. Dummer R The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma J. Am. Acad. Dermatol. 2016 75 113 125.e115 27067394 10.1016/j.jaad.2016.02.1226 Dummer, R. et al. The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J. Am. Acad. Dermatol. 75 , 113–125.e115 (2016). 27067394 10.1016/j.jaad.2016.02.1226

426. Migden M Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial Lancet Oncol. 2015 16 716 728 25981810 10.1016/S1470-2045(15)70100-2 Migden, M. et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 16 , 716–728 (2015). 25981810 10.1016/S1470-2045(15)70100-2

427. Nguyen A Xie P Litvinov IV Lefrançois P Efficacy and safety of sonic hedgehog inhibitors in basal cell carcinomas: an updated systematic review and meta-analysis (2009–2022) Am. J. Clin. Dermatol. 2023 24 359 374 36795228 10.1007/s40257-023-00763-x Nguyen, A., Xie, P., Litvinov, I. V. & Lefrançois, P. Efficacy and safety of sonic hedgehog inhibitors in basal cell carcinomas: an updated systematic review and meta-analysis (2009–2022). Am. J. Clin. Dermatol. 24 , 359–374 (2023). 36795228 10.1007/s40257-023-00763-x

428. Kieran M Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma Neuro Oncol. 2017 19 1542 1552 28605510 10.1093/neuonc/nox109 PMC5737275 Kieran, M. et al. Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma. Neuro Oncol. 19 , 1542–1552 (2017). 28605510 10.1093/neuonc/nox109 PMC5737275

429. Stathis A Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors Invest. New Drugs 2017 35 766 772 28317088 10.1007/s10637-017-0454-z Stathis, A. et al. Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors. Invest. New Drugs 35 , 766–772 (2017). 28317088 10.1007/s10637-017-0454-z

430. Rodon J A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors Clin. Cancer Res. 2014 20 1900 1909 24523439 10.1158/1078-0432.CCR-13-1710 Rodon, J. et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin. Cancer Res. 20 , 1900–1909 (2014). 24523439 10.1158/1078-0432.CCR-13-1710

431. Jain S Song R Xie J Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas Onco Targets Ther. 2017 10 1645 1653 28352196 10.2147/OTT.S130910 PMC5360396 Jain, S., Song, R. & Xie, J. Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. Onco Targets Ther. 10 , 1645–1653 (2017). 28352196 10.2147/OTT.S130910 PMC5360396

432. Gutzmer R Key clinical adverse events in patients with advanced basal cell carcinoma treated with sonidegib or vismodegib: a post hoc analysis Dermatol. Ther. (Heidelb.) 2021 11 1839 1849 34490549 10.1007/s13555-021-00588-8 PMC8484385 Gutzmer, R. et al. Key clinical adverse events in patients with advanced basal cell carcinoma treated with sonidegib or vismodegib: a post hoc analysis. Dermatol. Ther. (Heidelb.) 11 , 1839–1849 (2021). 34490549 10.1007/s13555-021-00588-8 PMC8484385

433. Tremblay M Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926) J. Med. Chem. 2009 52 4400 4418 19522463 10.1021/jm900305z Tremblay, M. et al. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J. Med. Chem. 52 , 4400–4418 (2009). 19522463 10.1021/jm900305z

434. Campbell V Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth Mol. Cancer Ther. 2014 13 1259 1269 24634412 10.1158/1535-7163.MCT-13-0731 Campbell, V. et al. Hedgehog pathway inhibition in chondrosarcoma using the smoothened inhibitor IPI-926 directly inhibits sarcoma cell growth. Mol. Cancer Ther. 13 , 1259–1269 (2014). 24634412 10.1158/1535-7163.MCT-13-0731

435. McCann C Inhibition of hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model PloS One 2011 6 e28077 22140510 10.1371/journal.pone.0028077 PMC3226669 McCann, C. et al. Inhibition of hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model. PloS One 6 , e28077 (2011). 22140510 10.1371/journal.pone.0028077 PMC3226669

436. Lo W Involvement and targeted intervention of dysregulated hedgehog signaling in osteosarcoma Cancer 2014 120 537 547 24151134 10.1002/cncr.28439 Lo, W. et al. Involvement and targeted intervention of dysregulated hedgehog signaling in osteosarcoma. Cancer 120 , 537–547 (2014). 24151134 10.1002/cncr.28439

437. Lin T Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926 PloS One 2010 5 e15262 21203400 10.1371/journal.pone.0015262 PMC3011010 Lin, T. et al. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926. PloS One 5 , e15262 (2010). 21203400 10.1371/journal.pone.0015262 PMC3011010

438. Lee M Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model Proc. Natl Acad. Sci. USA 2012 109 7859 7864 22550175 10.1073/pnas.1114718109 PMC3356655 Lee, M. et al. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc. Natl Acad. Sci. USA 109 , 7859–7864 (2012). 22550175 10.1073/pnas.1114718109 PMC3356655

439. Ko A A phase I study of FOLFIRINOX Plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma Pancreas 2016 45 370 375 26390428 10.1097/MPA.0000000000000458 PMC5908466 Ko, A. et al. A phase I study of FOLFIRINOX Plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 45 , 370–375 (2016). 26390428 10.1097/MPA.0000000000000458 PMC5908466

440. Bowles D A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma Oral. Oncol. 2016 53 74 79 26705064 10.1016/j.oraloncology.2015.11.014 PMC5676309 Bowles, D. et al. A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma. Oral. Oncol. 53 , 74–79 (2016). 26705064 10.1016/j.oraloncology.2015.11.014 PMC5676309

441. Jimeno A Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors Clin. Cancer Res. 2013 19 2766 2774 23575478 10.1158/1078-0432.CCR-12-3654 PMC3694426 Jimeno, A. et al. Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin. Cancer Res. 19 , 2766–2774 (2013). 23575478 10.1158/1078-0432.CCR-12-3654 PMC3694426

442. Munchhof M Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened ACS Med. Chem. Lett. 2012 3 106 111 24900436 10.1021/ml2002423 PMC4025788 Munchhof, M. et al. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med. Chem. Lett. 3 , 106–111 (2012). 24900436 10.1021/ml2002423 PMC4025788

443. Cortes J Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome Leukemia 2019 33 379 389 30555165 10.1038/s41375-018-0312-9 PMC6365492 Cortes, J. et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 33 , 379–389 (2019). 30555165 10.1038/s41375-018-0312-9 PMC6365492

444. Wagner A A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors Clin. Cancer Res. 2015 21 1044 1051 25388167 10.1158/1078-0432.CCR-14-1116 Wagner, A. et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 21 , 1044–1051 (2015). 25388167 10.1158/1078-0432.CCR-14-1116

445. Bendell J Phase I study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment-naïve and previously treated basal cell carcinoma Clin. Cancer Res. 2018 24 2082 2091 29483143 10.1158/1078-0432.CCR-17-0723 PMC6422158 Bendell, J. et al. Phase I study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment-naïve and previously treated basal cell carcinoma. Clin. Cancer Res. 24 , 2082–2091 (2018). 29483143 10.1158/1078-0432.CCR-17-0723 PMC6422158

446. Azaro A A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors Invest. New Drugs 2021 39 1089 1098 33686452 10.1007/s10637-021-01094-6 Azaro, A. et al. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest. New Drugs 39 , 1089–1098 (2021). 33686452 10.1007/s10637-021-01094-6

447. Zaidi A Smoothened inhibition leads to decreased proliferation and induces apoptosis in esophageal adenocarcinoma cells Cancer Invest. 2013 31 480 489 23915072 10.3109/07357907.2013.820317 Zaidi, A. et al. Smoothened inhibition leads to decreased proliferation and induces apoptosis in esophageal adenocarcinoma cells. Cancer Invest. 31 , 480–489 (2013). 23915072 10.3109/07357907.2013.820317

448. Nguyen J New ameloblastoma cell lines enable preclinical study of targeted therapies J. Dent. Res. 2022 101 1517 1525 35689405 10.1177/00220345221100773 PMC9608093 Nguyen, J. et al. New ameloblastoma cell lines enable preclinical study of targeted therapies. J. Dent. Res. 101 , 1517–1525 (2022). 35689405 10.1177/00220345221100773 PMC9608093

449. Lauressergues E Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model Pharmacol. Res. Perspect. 2016 4 e00214 27069629 10.1002/prp2.214 PMC4804317 Lauressergues, E. et al. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol. Res. Perspect. 4 , e00214 (2016). 27069629 10.1002/prp2.214 PMC4804317

450. Ohashi T Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility Bioorg. Med. Chem. 2012 20 5507 5517 22898254 10.1016/j.bmc.2012.07.034 Ohashi, T. et al. Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility. Bioorg. Med. Chem. 20 , 5507–5517 (2012). 22898254 10.1016/j.bmc.2012.07.034

451. Ibuki N TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling Int. J. Cancer 2013 133 1955 1966 23564295 10.1002/ijc.28193 Ibuki, N. et al. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int. J. Cancer 133 , 1955–1966 (2013). 23564295 10.1002/ijc.28193

452. Kogame A Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice Drug Metab. Dispos. 2013 41 727 734 23298863 10.1124/dmd.112.049650 Kogame, A. et al. Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. Drug Metab. Dispos. 41 , 727–734 (2013). 23298863 10.1124/dmd.112.049650

453. Goldman J Phase I dose-escalation trial of the oral investigational hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors Clin. Cancer Res. 2015 21 1002 1009 25501576 10.1158/1078-0432.CCR-14-1234 Goldman, J. et al. Phase I dose-escalation trial of the oral investigational hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. Clin. Cancer Res. 21 , 1002–1009 (2015). 25501576 10.1158/1078-0432.CCR-14-1234

454. Spanakis E Aperis G Mylonakis E New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage Clin. Infect. Dis. 2006 43 1060 1068 16983621 10.1086/507891 Spanakis, E., Aperis, G. & Mylonakis, E. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin. Infect. Dis. 43 , 1060–1068 (2006). 16983621 10.1086/507891

455. Kim J Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth Cancer Cell 2010 17 388 399 20385363 10.1016/j.ccr.2010.02.027 PMC4039177 Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17 , 388–399 (2010). 20385363 10.1016/j.ccr.2010.02.027 PMC4039177

456. Freitas R Inhibition of CAL27 oral squamous carcinoma cell by targeting hedgehog pathway with vismodegib or itraconazole Front. Oncol. 2020 10 563838 33312948 10.3389/fonc.2020.563838 PMC7703359 Freitas, R. et al. Inhibition of CAL27 oral squamous carcinoma cell by targeting hedgehog pathway with vismodegib or itraconazole. Front. Oncol. 10 , 563838 (2020). 33312948 10.3389/fonc.2020.563838 PMC7703359

457. Hu Q Itraconazole induces apoptosis and cell cycle arrest via inhibiting hedgehog signaling in gastric cancer cells J. Exp. Clin. Cancer Res. 2017 36 50 28399898 10.1186/s13046-017-0526-0 PMC5387201 Hu, Q. et al. Itraconazole induces apoptosis and cell cycle arrest via inhibiting hedgehog signaling in gastric cancer cells. J. Exp. Clin. Cancer Res. 36 , 50 (2017). 28399898 10.1186/s13046-017-0526-0 PMC5387201

458. You M Targeting of the hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro J. Thorac. Cardiovasc. Surg. 2014 147 508 516 24094913 10.1016/j.jtcvs.2013.08.035 You, M. et al. Targeting of the hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. J. Thorac. Cardiovasc. Surg. 147 , 508–516 (2014). 24094913 10.1016/j.jtcvs.2013.08.035

459. Kim D Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma J. Clin. Oncol. 2014 32 745 751 24493717 10.1200/JCO.2013.49.9525 Kim, D. et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J. Clin. Oncol. 32 , 745–751 (2014). 24493717 10.1200/JCO.2013.49.9525

460. Solinas A Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity J. Med. Chem. 2012 55 1559 1571 22268551 10.1021/jm2013369 Solinas, A. et al. Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity. J. Med. Chem. 55 , 1559–1571 (2012). 22268551 10.1021/jm2013369

461. Hoch L MRT-92 inhibits hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the smoothened receptor FASEB J. 2015 29 1817 1829 25636740 10.1096/fj.14-267849 PMC4415011 Hoch, L. et al. MRT-92 inhibits hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the smoothened receptor. FASEB J. 29 , 1817–1829 (2015). 25636740 10.1096/fj.14-267849 PMC4415011

462. Pietrobono S Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe Cell Death Dis. 2018 9 142 29396391 10.1038/s41419-017-0142-0 PMC5833413 Pietrobono, S. et al. Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe. Cell Death Dis. 9 , 142 (2018). 29396391 10.1038/s41419-017-0142-0 PMC5833413

463. Pietrobono S Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma Oncogene 2021 40 3799 3814 33958721 10.1038/s41388-021-01783-9 PMC8175236 Pietrobono, S. et al. Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma. Oncogene 40 , 3799–3814 (2021). 33958721 10.1038/s41388-021-01783-9 PMC8175236

464. Rohner A Effective targeting of hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective smoothened antagonist that penetrates the blood-brain barrier Mol. Cancer Ther. 2012 11 57 65 22084163 10.1158/1535-7163.MCT-11-0691 Rohner, A. et al. Effective targeting of hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective smoothened antagonist that penetrates the blood-brain barrier. Mol. Cancer Ther. 11 , 57–65 (2012). 22084163 10.1158/1535-7163.MCT-11-0691

465. Zhang M Gao L Ye Y Li X Advances in glioma-associated oncogene (GLI) inhibitors for cancer therapy Invest. New Drugs 2022 40 370 388 34837604 10.1007/s10637-021-01187-2 Zhang, M., Gao, L., Ye, Y. & Li, X. Advances in glioma-associated oncogene (GLI) inhibitors for cancer therapy. Invest. New Drugs 40 , 370–388 (2022). 34837604 10.1007/s10637-021-01187-2

466. Sharpe H Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma Cancer Cell 2015 27 327 341 25759019 10.1016/j.ccell.2015.02.001 PMC5675004 Sharpe, H. et al. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell 27 , 327–341 (2015). 25759019 10.1016/j.ccell.2015.02.001 PMC5675004

467. Atwood S Smoothened variants explain the majority of drug resistance in basal cell carcinoma Cancer Cell 2015 27 342 353 25759020 10.1016/j.ccell.2015.02.002 PMC4357167 Atwood, S. et al. Smoothened variants explain the majority of drug resistance in basal cell carcinoma. Cancer Cell 27 , 342–353 (2015). 25759020 10.1016/j.ccell.2015.02.002 PMC4357167

468. Lauth M Bergström A Shimokawa T Toftgård R Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists Proc. Natl Acad. Sci. USA 2007 104 8455 8460 17494766 10.1073/pnas.0609699104 PMC1866313 Lauth, M., Bergström, A., Shimokawa, T. & Toftgård, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104 , 8455–8460 (2007). 17494766 10.1073/pnas.0609699104 PMC1866313

469. Sharma A Sonic hedgehog pathway activation regulates cervical cancer stem cell characteristics during epithelial to mesenchymal transition J. Cell Physiol. 2019 234 15726 15741 30714153 10.1002/jcp.28231 Sharma, A. et al. Sonic hedgehog pathway activation regulates cervical cancer stem cell characteristics during epithelial to mesenchymal transition. J. Cell Physiol. 234 , 15726–15741 (2019). 30714153 10.1002/jcp.28231

470. Hou X Inhibition of hedgehog signaling by GANT58 induces apoptosis and shows synergistic antitumor activity with AKT inhibitor in acute T cell leukemia cells Biochimie 2014 101 50 59 24394624 10.1016/j.biochi.2013.12.019 Hou, X. et al. Inhibition of hedgehog signaling by GANT58 induces apoptosis and shows synergistic antitumor activity with AKT inhibitor in acute T cell leukemia cells. Biochimie 101 , 50–59 (2014). 24394624 10.1016/j.biochi.2013.12.019

471. Oladapo H Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells Cancer Lett. 2017 411 136 149 28965853 10.1016/j.canlet.2017.09.033 PMC5720365 Oladapo, H. et al. Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells. Cancer Lett. 411 , 136–149 (2017). 28965853 10.1016/j.canlet.2017.09.033 PMC5720365

472. Zubčić V GANT61 and Lithium Chloride inhibit the growth of head and neck cancer cell lines through the regulation of GLI3 processing by GSK3β Int. J. Mol. Sci. 2020 21 6410 32899202 10.3390/ijms21176410 PMC7504345 Zubčić, V. et al. GANT61 and Lithium Chloride inhibit the growth of head and neck cancer cell lines through the regulation of GLI3 processing by GSK3β. Int. J. Mol. Sci. 21 , 6410 (2020). 32899202 10.3390/ijms21176410 PMC7504345

473. Harada K Ohashi R Naito K Kanki K Hedgehog signal inhibitor GANT61 inhibits the malignant behavior of undifferentiated hepatocellular carcinoma cells by targeting non-canonical GLI signaling Int. J. Mol. Sci. 2020 21 3126 32354204 10.3390/ijms21093126 PMC7247445 Harada, K., Ohashi, R., Naito, K. & Kanki, K. Hedgehog signal inhibitor GANT61 inhibits the malignant behavior of undifferentiated hepatocellular carcinoma cells by targeting non-canonical GLI signaling. Int. J. Mol. Sci. 21 , 3126 (2020). 32354204 10.3390/ijms21093126 PMC7247445

474. Sneha S The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary Cell Oncol. (Dordr.) 2020 43 601 616 32382997 10.1007/s13402-020-00504-w PMC12990732 Sneha, S. et al. The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary. Cell Oncol. (Dordr.) 43 , 601–616 (2020). 32382997 10.1007/s13402-020-00504-w PMC12990732

475. Yang H Inhibition of Gli1-mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway Oncol. Lett. 2017 14 7970 7976 29250185 10.3892/ol.2017.7254 PMC5727603 Yang, H. et al. Inhibition of Gli1-mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway. Oncol. Lett. 14 , 7970–7976 (2017). 29250185 10.3892/ol.2017.7254 PMC5727603

476. Chang Y The inhibitory effect and safety of GANT61 on HeLa cells in nude mice Exp. Mol. Pathol. 2020 113 104352 31809711 10.1016/j.yexmp.2019.104352 Chang, Y. et al. The inhibitory effect and safety of GANT61 on HeLa cells in nude mice. Exp. Mol. Pathol. 113 , 104352 (2020). 31809711 10.1016/j.yexmp.2019.104352

477. Chang J Downregulation of Rab23 in prostate cancer inhibits tumor growth in vitro and in vivo Oncol. Res. 2017 25 241 248 28277196 10.3727/096504016X14742891049118 PMC7840735 Chang, J. et al. Downregulation of Rab23 in prostate cancer inhibits tumor growth in vitro and in vivo. Oncol. Res. 25 , 241–248 (2017). 28277196 10.3727/096504016X14742891049118 PMC7840735

478. Azatyan A RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma via JNK-dependent but p53-independent mechanism Cancer Lett. 2019 442 341 350 30447254 10.1016/j.canlet.2018.11.005 Azatyan, A. et al. RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma via JNK-dependent but p53-independent mechanism. Cancer Lett. 442 , 341–350 (2019). 30447254 10.1016/j.canlet.2018.11.005

479. Calcaterra A Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61 J. Enzym. Inhib. Med. Chem. 2018 33 349 358 10.1080/14756366.2017.1419221 PMC6009951 29338454 Calcaterra, A. et al. Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61. J. Enzym. Inhib. Med. Chem. 33 , 349–358 (2018). 10.1080/14756366.2017.1419221 PMC6009951 29338454

480. Cicconi L Lo-Coco F Current management of newly diagnosed acute promyelocytic leukemia Ann. Oncol. 2016 27 1474 1481 27084953 10.1093/annonc/mdw171 Cicconi, L. & Lo-Coco, F. Current management of newly diagnosed acute promyelocytic leukemia. Ann. Oncol. 27 , 1474–1481 (2016). 27084953 10.1093/annonc/mdw171

481. Jeanne M PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3 Cancer Cell 2010 18 88 98 20609355 10.1016/j.ccr.2010.06.003 Jeanne, M. et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 18 , 88–98 (2010). 20609355 10.1016/j.ccr.2010.06.003

482. Kim J Arsenic antagonizes the hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector Proc. Natl Acad. Sci. USA 2010 107 13432 13437 20624968 10.1073/pnas.1006822107 PMC2922148 Kim, J. et al. Arsenic antagonizes the hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc. Natl Acad. Sci. USA 107 , 13432–13437 (2010). 20624968 10.1073/pnas.1006822107 PMC2922148

483. Zhang X Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML Science 2010 328 240 243 20378816 10.1126/science.1183424 Zhang, X. et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328 , 240–243 (2010). 20378816 10.1126/science.1183424

484. Beauchamp E Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway J. Clin. Invest. 2011 121 148 160 21183792 10.1172/JCI42874 PMC3007144 Beauchamp, E. et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J. Clin. Invest. 121 , 148–160 (2011). 21183792 10.1172/JCI42874 PMC3007144

485. Yang D Arsenic trioxide inhibits the hedgehog pathway which is aberrantly activated in acute promyelocytic leukemia Acta Haematol. 2013 130 260 267 23867347 10.1159/000351603 Yang, D. et al. Arsenic trioxide inhibits the hedgehog pathway which is aberrantly activated in acute promyelocytic leukemia. Acta Haematol. 130 , 260–267 (2013). 23867347 10.1159/000351603

486. Han J Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli Onco Targets Ther. 2013 6 1129 1138 23990729 10.2147/OTT.S49148 PMC3753152 Han, J. et al. Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. Onco Targets Ther. 6 , 1129–1138 (2013). 23990729 10.2147/OTT.S49148 PMC3753152

487. Nakamura S Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation PloS One 2013 8 e69466 23861973 10.1371/journal.pone.0069466 PMC3704531 Nakamura, S. et al. Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation. PloS One 8 , e69466 (2013). 23861973 10.1371/journal.pone.0069466 PMC3704531

488. Boehme K Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma Int. J. Oncol. 2016 48 801 812 26676886 10.3892/ijo.2015.3293 Boehme, K. et al. Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma. Int. J. Oncol. 48 , 801–812 (2016). 26676886 10.3892/ijo.2015.3293

489. Douer D Tallman M Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies J. Clin. Oncol. 2005 23 2396 2410 15800332 10.1200/JCO.2005.10.217 Douer, D. & Tallman, M. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J. Clin. Oncol. 23 , 2396–2410 (2005). 15800332 10.1200/JCO.2005.10.217

490. Yu M Current advances of nanomedicines delivering arsenic trioxide for enhanced tumor therapy Pharmaceutics 2022 14 743 35456577 10.3390/pharmaceutics14040743 PMC9026299 Yu, M. et al. Current advances of nanomedicines delivering arsenic trioxide for enhanced tumor therapy. Pharmaceutics 14 , 743 (2022). 35456577 10.3390/pharmaceutics14040743 PMC9026299

491. Kramann R Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis J. Clin. Invest. 2015 125 2935 2951 26193634 10.1172/JCI74929 PMC4563736 Kramann, R. et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J. Clin. Invest. 125 , 2935–2951 (2015). 26193634 10.1172/JCI74929 PMC4563736

492. Mann K Wallner B Lossos I Miller WJ Darinaparsin: a novel organic arsenical with promising anticancer activity Expert Opin. Investig. Drugs 2009 18 1727 1734 19780704 10.1517/13543780903282759 Mann, K., Wallner, B., Lossos, I. & Miller, W. J. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin. Investig. Drugs 18 , 1727–1734 (2009). 19780704 10.1517/13543780903282759

493. Frampton J Darinaparsin: first approval Drugs 2022 82 1603 1609 36331780 10.1007/s40265-022-01795-z Frampton, J. Darinaparsin: first approval. Drugs 82 , 1603–1609 (2022). 36331780 10.1007/s40265-022-01795-z

494. Ravi D The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models Clin. Cancer Res. 2014 20 6023 6033 25316819 10.1158/1078-0432.CCR-14-1532 PMC4281835 Ravi, D. et al. The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models. Clin. Cancer Res. 20 , 6023–6033 (2014). 25316819 10.1158/1078-0432.CCR-14-1532 PMC4281835

495. Tian J Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer Clin. Cancer Res. 2012 18 3366 3376 22535156 10.1158/1078-0432.CCR-11-3179 PMC5518752 Tian, J. et al. Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. Clin. Cancer Res. 18 , 3366–3376 (2012). 22535156 10.1158/1078-0432.CCR-11-3179 PMC5518752

496. Bansal N Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling Mol. Cancer Ther. 2015 14 23 30 25381261 10.1158/1535-7163.MCT-13-1040 Bansal, N. et al. Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling. Mol. Cancer Ther. 14 , 23–30 (2015). 25381261 10.1158/1535-7163.MCT-13-1040

497. Tsimberidou A A phase I clinical trial of darinaparsin in patients with refractory solid tumors Clin. Cancer Res. 2009 15 4769 4776 19584162 10.1158/1078-0432.CCR-08-2984 Tsimberidou, A. et al. A phase I clinical trial of darinaparsin in patients with refractory solid tumors. Clin. Cancer Res. 15 , 4769–4776 (2009). 19584162 10.1158/1078-0432.CCR-08-2984

498. Hosein P A multicenter phase II study of darinaparsin in relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma Am. J. Hematol. 2012 87 111 114 22081459 10.1002/ajh.22232 Hosein, P. et al. A multicenter phase II study of darinaparsin in relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma. Am. J. Hematol. 87 , 111–114 (2012). 22081459 10.1002/ajh.22232

499. Hyman J Small-molecule inhibitors reveal multiple strategies for hedgehog pathway blockade Proc. Natl Acad. Sci. USA 2009 106 14132 14137 19666565 10.1073/pnas.0907134106 PMC2721821 Hyman, J. et al. Small-molecule inhibitors reveal multiple strategies for hedgehog pathway blockade. Proc. Natl Acad. Sci. USA 106 , 14132–14137 (2009). 19666565 10.1073/pnas.0907134106 PMC2721821

500. Kaur G Bromodomain and hedgehog pathway targets in small cell lung cancer Cancer Lett. 2016 371 225 239 26683772 10.1016/j.canlet.2015.12.001 PMC4738144 Kaur, G. et al. Bromodomain and hedgehog pathway targets in small cell lung cancer. Cancer Lett. 371 , 225–239 (2016). 26683772 10.1016/j.canlet.2015.12.001 PMC4738144

501. Jeng K Glioma-associated oncogene homolog inhibitors have the potential of suppressing cancer stem cells of breast cancer Int. J. Mol. Sci. 2018 19 1375 29734730 10.3390/ijms19051375 PMC5983844 Jeng, K. et al. Glioma-associated oncogene homolog inhibitors have the potential of suppressing cancer stem cells of breast cancer. Int. J. Mol. Sci. 19 , 1375 (2018). 29734730 10.3390/ijms19051375 PMC5983844

502. Xiang W Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis Oncol. Rep. 2014 32 1622 1630 25110171 10.3892/or.2014.3372 Xiang, W. et al. Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis. Oncol. Rep. 32 , 1622–1630 (2014). 25110171 10.3892/or.2014.3372

503. Chenna V A polymeric nanoparticle encapsulated small-molecule inhibitor of hedgehog signaling (NanoHHI) bypasses secondary mutational resistance to smoothened antagonists Mol. Cancer Ther. 2012 11 165 173 22027695 10.1158/1535-7163.MCT-11-0341 PMC3256300 Chenna, V. et al. A polymeric nanoparticle encapsulated small-molecule inhibitor of hedgehog signaling (NanoHHI) bypasses secondary mutational resistance to smoothened antagonists. Mol. Cancer Ther. 11 , 165–173 (2012). 22027695 10.1158/1535-7163.MCT-11-0341 PMC3256300

504. Bao C Kramata P Lee H Suh N Regulation of hedgehog signaling in cancer by natural and dietary compounds Mol. Nutr. Food Res. 2018 62 1700621 10.1002/mnfr.201700621 PMC6677142 29164817 Bao, C., Kramata, P., Lee, H. & Suh, N. Regulation of hedgehog signaling in cancer by natural and dietary compounds. Mol. Nutr. Food Res. 62 , 1700621 (2018). 10.1002/mnfr.201700621 PMC6677142 29164817

505. Deberardinis A Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors J. Med. Chem. 2014 57 3724 3736 24730984 10.1021/jm401812d Deberardinis, A. et al. Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors. J. Med. Chem. 57 , 3724–3736 (2014). 24730984 10.1021/jm401812d

506. Tang J Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas Cancer Prev. Res. (Philos.) 2011 4 744 751 10.1158/1940-6207.CAPR-10-0285 PMC3088781 21436386 Tang, J. et al. Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. Cancer Prev. Res. (Philos.) 4 , 744–751 (2011). 10.1158/1940-6207.CAPR-10-0285 PMC3088781 21436386

507. Sharma U Role of Hedgehog and Hippo signaling pathways in cancer: a special focus on non-coding RNAs Pharmacol. Res. 2022 186 106523 36377125 10.1016/j.phrs.2022.106523 Sharma, U. et al. Role of Hedgehog and Hippo signaling pathways in cancer: a special focus on non-coding RNAs. Pharmacol. Res. 186 , 106523 (2022). 36377125 10.1016/j.phrs.2022.106523

508. Sargazi M The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer Med. Oncol. 2022 39 127 35716241 10.1007/s12032-022-01710-2 Sargazi, M. et al. The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer. Med. Oncol. 39 , 127 (2022). 35716241 10.1007/s12032-022-01710-2

509. Chen Y Li Z Chen X Zhang S Long non-coding RNAs: from disease code to drug role Acta Pharmacol. Sin. B 2021 11 340 354 10.1016/j.apsb.2020.10.001 PMC7893121 33643816 Chen, Y., Li, Z., Chen, X. & Zhang, S. Long non-coding RNAs: from disease code to drug role. Acta Pharmacol. Sin. B 11 , 340–354 (2021). 10.1016/j.apsb.2020.10.001 PMC7893121 33643816

510. Takezaki T Essential role of the hedgehog signaling pathway in human glioma-initiating cells Cancer Sci. 2011 102 1306 1312 21453386 10.1111/j.1349-7006.2011.01943.x PMC11158128 Takezaki, T. et al. Essential role of the hedgehog signaling pathway in human glioma-initiating cells. Cancer Sci. 102 , 1306–1312 (2011). 21453386 10.1111/j.1349-7006.2011.01943.x PMC11158128

511. Zhou J Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target Cancer Lett. 2016 370 313 323 26577809 10.1016/j.canlet.2015.11.006 Zhou, J. et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 370 , 313–323 (2016). 26577809 10.1016/j.canlet.2015.11.006

512. Vecchiotti D Elevated NF-κB/SHh/GLI1 signature denotes a worse prognosis and represent a novel potential therapeutic target in advanced prostate cancer Cells 2022 11 2118 35805202 10.3390/cells11132118 PMC9266159 Vecchiotti, D. et al. Elevated NF-κB/SHh/GLI1 signature denotes a worse prognosis and represent a novel potential therapeutic target in advanced prostate cancer. Cells 11 , 2118 (2022). 35805202 10.3390/cells11132118 PMC9266159

513. Cho K Pharmacological inhibition of sonic hedgehog signaling suppresses tumor development in a murine model of intrahepatic cholangiocarcinoma Int. J. Mol. Sci. 2021 22 13214 34948011 10.3390/ijms222413214 PMC8707521 Cho, K. et al. Pharmacological inhibition of sonic hedgehog signaling suppresses tumor development in a murine model of intrahepatic cholangiocarcinoma. Int. J. Mol. Sci. 22 , 13214 (2021). 34948011 10.3390/ijms222413214 PMC8707521

514. Szczepny A The role of canonical and non-canonical hedgehog signaling in tumor progression in a mouse model of small cell lung cancer Oncogene 2017 36 5544 5550 28581526 10.1038/onc.2017.173 PMC5623150 Szczepny, A. et al. The role of canonical and non-canonical hedgehog signaling in tumor progression in a mouse model of small cell lung cancer. Oncogene 36 , 5544–5550 (2017). 28581526 10.1038/onc.2017.173 PMC5623150

515. Zhou C GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia Cell Death Dis. 2021 12 231 33658491 10.1038/s41419-021-03504-2 PMC7930050 Zhou, C. et al. GLI1 reduces drug sensitivity by regulating cell cycle through PI3K/AKT/GSK3/CDK pathway in acute myeloid leukemia. Cell Death Dis. 12 , 231 (2021). 33658491 10.1038/s41419-021-03504-2 PMC7930050

516. Romitti M MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma Endocr. Relat. Cancer 2016 23 135 146 26825960 10.1530/ERC-15-0162 Romitti, M. et al. MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Endocr. Relat. Cancer 23 , 135–146 (2016). 26825960 10.1530/ERC-15-0162

517. Wang J Berberine, a natural compound, suppresses Hedgehog signaling pathway activity and cancer growth BMC Cancer 2015 15 595 26296751 10.1186/s12885-015-1596-z PMC4546096 Wang, J. et al. Berberine, a natural compound, suppresses Hedgehog signaling pathway activity and cancer growth. BMC Cancer 15 , 595 (2015). 26296751 10.1186/s12885-015-1596-z PMC4546096

518. Li X Cynanbungeigenin C and D, a pair of novel epimers from Cynanchum bungei, suppress hedgehog pathway-dependent medulloblastoma by blocking signaling at the level of Gli Cancer Lett. 2018 420 195 207 29425683 10.1016/j.canlet.2018.02.005 Li, X. et al. Cynanbungeigenin C and D, a pair of novel epimers from Cynanchum bungei, suppress hedgehog pathway-dependent medulloblastoma by blocking signaling at the level of Gli. Cancer Lett. 420 , 195–207 (2018). 29425683 10.1016/j.canlet.2018.02.005

519. Singh S Selective targeting of the hedgehog signaling pathway by PBM nanoparticles in docetaxel-resistant prostate cancer Cells 2020 9 1976 32867229 10.3390/cells9091976 PMC7563377 Singh, S. et al. Selective targeting of the hedgehog signaling pathway by PBM nanoparticles in docetaxel-resistant prostate cancer. Cells 9 , 1976 (2020). 32867229 10.3390/cells9091976 PMC7563377

520. Gao Q Yuan Y Gan H Peng Q Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis Oncol. Lett. 2015 9 2381 2387 26137075 10.3892/ol.2015.2988 PMC4467343 Gao, Q., Yuan, Y., Gan, H. & Peng, Q. Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis. Oncol. Lett. 9 , 2381–2387 (2015). 26137075 10.3892/ol.2015.2988 PMC4467343

521. Qin Y Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the hedgehog signaling pathway Mol. Med. Rep. 2014 10 2563 2567 25190613 10.3892/mmr.2014.2511 Qin, Y. et al. Effect of resveratrol on proliferation and apoptosis of human pancreatic cancer MIA PaCa-2 cells may involve inhibition of the hedgehog signaling pathway. Mol. Med. Rep. 10 , 2563–2567 (2014). 25190613 10.3892/mmr.2014.2511

522. Du W Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo CNS Neurosci. Ther. 2013 19 926 936 24165291 10.1111/cns.12163 PMC6493544 Du, W. et al. Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo. CNS Neurosci. Ther. 19 , 926–936 (2013). 24165291 10.1111/cns.12163 PMC6493544

523. Zhu J Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and sonic hedgehog pathways Phytother. Res. 2017 31 680 688 28198062 10.1002/ptr.5791 Zhu, J. et al. Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and sonic hedgehog pathways. Phytother. Res. 31 , 680–688 (2017). 28198062 10.1002/ptr.5791

524. Cao L Curcumin inhibits hypoxia-induced epithelial‑mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway Oncol. Rep. 2016 35 3728 3734 27035865 10.3892/or.2016.4709 Cao, L. et al. Curcumin inhibits hypoxia-induced epithelial‑mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway. Oncol. Rep. 35 , 3728–3734 (2016). 27035865 10.3892/or.2016.4709

525. Elamin M Curcumin inhibits the sonic hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells Mol. Carcinog. 2010 49 302 314 20025076 10.1002/mc.20604 Elamin, M. et al. Curcumin inhibits the sonic hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol. Carcinog. 49 , 302–314 (2010). 20025076 10.1002/mc.20604

526. Sur S Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice Toxicol. Appl. Pharmacol. 2016 300 34 46 27058323 10.1016/j.taap.2016.03.016 Sur, S. et al. Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice. Toxicol. Appl. Pharmacol. 300 , 34–46 (2016). 27058323 10.1016/j.taap.2016.03.016

527. Tang S Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics Int. J. Cancer 2012 131 30 40 21796625 10.1002/ijc.26323 PMC3480310 Tang, S. et al. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int. J. Cancer 131 , 30–40 (2012). 21796625 10.1002/ijc.26323 PMC3480310

528. Tang G (-)-Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells J. Cancer Res. Clin. Oncol. 2010 136 1179 1185 20127255 10.1007/s00432-010-0765-3 PMC11828257 Tang, G. et al. (-)-Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells. J. Cancer Res. Clin. Oncol. 136 , 1179–1185 (2010). 20127255 10.1007/s00432-010-0765-3 PMC11828257

529. Zhao M Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice Cancer Lett. 2013 337 210 217 23684930 10.1016/j.canlet.2013.05.009 Zhao, M. et al. Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Lett. 337 , 210–217 (2013). 23684930 10.1016/j.canlet.2013.05.009

530. Luo J Saikosaponin B1 and Saikosaponin D inhibit tumor growth in medulloblastoma allograft mice via inhibiting the Hedgehog signaling pathway J. Nat. Med. 2022 76 584 593 35171398 10.1007/s11418-022-01603-8 Luo, J. et al. Saikosaponin B1 and Saikosaponin D inhibit tumor growth in medulloblastoma allograft mice via inhibiting the Hedgehog signaling pathway. J. Nat. Med. 76 , 584–593 (2022). 35171398 10.1007/s11418-022-01603-8

531. Fan P Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway Stem Cell Res. Ther. 2013 4 146 24331293 10.1186/scrt357 PMC4054948 Fan, P. et al. Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway. Stem Cell Res. Ther. 4 , 146 (2013). 24331293 10.1186/scrt357 PMC4054948

532. Zhang L Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway Cancer Lett. 2012 323 48 57 22484470 10.1016/j.canlet.2012.03.037 Zhang, L. et al. Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett. 323 , 48–57 (2012). 22484470 10.1016/j.canlet.2012.03.037

533. Infante P Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors EMBO J. 2015 34 200 217 25476449 10.15252/embj.201489213 PMC4298015 Infante, P. et al. Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors. EMBO J. 34 , 200–217 (2015). 25476449 10.15252/embj.201489213 PMC4298015

534. Ma Z Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in renal cell carcinoma Oncol. Rep. 2015 34 2461 2468 26323996 10.3892/or.2015.4224 Ma, Z. et al. Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in renal cell carcinoma. Oncol. Rep. 34 , 2461–2468 (2015). 26323996 10.3892/or.2015.4224

535. Qiu P Inoscavin A, a pyrone compound isolated from a Sanghuangporus vaninii extract, inhibits colon cancer cell growth and induces cell apoptosis via the hedgehog signaling pathway Phytomedicine 2022 96 153852 35026508 10.1016/j.phymed.2021.153852 Qiu, P. et al. Inoscavin A, a pyrone compound isolated from a Sanghuangporus vaninii extract, inhibits colon cancer cell growth and induces cell apoptosis via the hedgehog signaling pathway. Phytomedicine 96 , 153852 (2022). 35026508 10.1016/j.phymed.2021.153852

536. Rifai Y Acoschimperoside P, 2’-acetate: a Hedgehog signaling inhibitory constituent from Vallaris glabra J. Nat. Med. 2011 65 629 632 21625949 10.1007/s11418-011-0530-1 Rifai, Y. et al. Acoschimperoside P, 2’-acetate: a Hedgehog signaling inhibitory constituent from Vallaris glabra. J. Nat. Med. 65 , 629–632 (2011). 10.1007/s11418-011-0530-1 21625949

537. Slusarz A Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer Cancer Res. 2010 70 3382 3390 10.1158/0008-5472.CAN-09-3012 20395211 Slusarz, A. et al. Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res. 70 , 3382–3390 (2010). 20395211 10.1158/0008-5472.CAN-09-3012

538. Arai M Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana Bioorg. Med. Chem. 2008 16 9420 9424 10.1016/j.bmc.2008.09.053 18842418 Arai, M. et al. Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg. Med. Chem. 16 , 9420–9424 (2008). 18842418 10.1016/j.bmc.2008.09.053

539. Zheng W Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway Oncol. Lett. 2016 12 2761 2765 27698853 10.3892/ol.2016.4928 PMC5038438 Zheng, W. et al. Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway. Oncol. Lett. 12 , 2761–2765 (2016). 27698853 10.3892/ol.2016.4928 PMC5038438

540. Lee H A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells Oncol. Lett. 2016 12 2912 2917 27698879 10.3892/ol.2016.4994 PMC5038360 Lee, H. et al. A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells. Oncol. Lett. 12 , 2912–2917 (2016). 27698879 10.3892/ol.2016.4994 PMC5038360

541. Hosoya T Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription Chembiochem 2008 9 1082 1092 10.1002/cbic.200700511 18357592 Hosoya, T. et al. Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem 9 , 1082–1092 (2008). 18357592 10.1002/cbic.200700511

542. Lin H Inhibition of Gli/hedgehog signaling in prostate cancer cells by “cancer bush” Sutherlandia frutescens extract Cell Biol. Int. 2016 40 131 142 26377232 10.1002/cbin.10544 PMC4713350 Lin, H. et al. Inhibition of Gli/hedgehog signaling in prostate cancer cells by “cancer bush” Sutherlandia frutescens extract. Cell Biol. Int. 40 , 131–142 (2016). 10.1002/cbin.10544 PMC4713350 26377232

543. Bao C Sulforaphene interferes with human breast cancer cell migration and invasion through inhibition of hedgehog signaling J. Agric. Food Chem. 2016 64 5515 5524 27327035 10.1021/acs.jafc.6b02195 Bao, C. et al. Sulforaphene interferes with human breast cancer cell migration and invasion through inhibition of hedgehog signaling. J. Agric. Food Chem. 64 , 5515–5524 (2016). 27327035 10.1021/acs.jafc.6b02195

544. Li S Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of sonic hedgehog-GLI pathway Mol. Cell Biochem. 2013 373 217 227 23129257 10.1007/s11010-012-1493-6 Li, S. et al. Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of sonic hedgehog-GLI pathway. Mol. Cell Biochem. 373 , 217–227 (2013). 23129257 10.1007/s11010-012-1493-6

545. Zheng S Li M Miao K Xu H lncRNA GAS5-promoted apoptosis in triple-negative breast cancer by targeting miR-378a-5p/SUFU signaling J. Cell Biochem. 2020 121 2225 2235 31692053 10.1002/jcb.29445 Zheng, S., Li, M., Miao, K. & Xu, H. lncRNA GAS5-promoted apoptosis in triple-negative breast cancer by targeting miR-378a-5p/SUFU signaling. J. Cell Biochem. 121 , 2225–2235 (2020). 10.1002/jcb.29445 31692053

546. Qiu S LncRNA EGOT decreases breast cancer cell viability and migration via inactivation of the Hedgehog pathway FEBS Open Bio. 2020 10 817 826 32150666 10.1002/2211-5463.12833 PMC7193175 Qiu, S. et al. LncRNA EGOT decreases breast cancer cell viability and migration via inactivation of the Hedgehog pathway. FEBS Open Bio. 10 , 817–826 (2020). 10.1002/2211-5463.12833 PMC7193175 32150666

547. Xu F Li H Hu C LIFR-AS1 modulates Sufu to inhibit cell proliferation and migration by miR-197-3p in breast cancer Biosci. Rep. 2019 39 BSR20180551 31127025 10.1042/BSR20180551 PMC6614576 Xu, F., Li, H. & Hu, C. LIFR-AS1 modulates Sufu to inhibit cell proliferation and migration by miR-197-3p in breast cancer. Biosci. Rep. 39 , BSR20180551 (2019). 10.1042/BSR20180551 PMC6614576 31127025

548. Xin L DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1 J. Cell Physiol. 2020 235 2643 2654 31517391 10.1002/jcp.29168 Xin, L. et al. DNA-methylation-mediated silencing of miR-7-5p promotes gastric cancer stem cell invasion via increasing Smo and Hes1. J. Cell Physiol. 235 , 2643–2654 (2020). 10.1002/jcp.29168 31517391

549. Li J miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3 Biochem. Biophys. Res. Commun. 2018 503 2101 2107 30100065 10.1016/j.bbrc.2018.07.166 Li, J. et al. miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3. Biochem. Biophys. Res. Commun. 503 , 2101–2107 (2018). 10.1016/j.bbrc.2018.07.166 30100065

550. Ferretti E Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells EMBO J. 2008 27 2616 2627 18756266 10.1038/emboj.2008.172 PMC2567402 Ferretti, E. et al. Concerted microRNA control of Hedgehog signalling in cerebellar neuronal progenitor and tumour cells. EMBO J. 27 , 2616–2627 (2008). 18756266 10.1038/emboj.2008.172 PMC2567402

551. Wang N miR-141-3p suppresses proliferation and promotes apoptosis by targeting GLI2 in osteosarcoma cells Oncol. Rep. 2018 39 747 754 29251328 10.3892/or.2017.6150 Wang, N. et al. miR-141-3p suppresses proliferation and promotes apoptosis by targeting GLI2 in osteosarcoma cells. Oncol. Rep. 39 , 747–754 (2018). 29251328 10.3892/or.2017.6150

552. Sun Z miR-202 suppresses proliferation and induces apoptosis of osteosarcoma cells by downregulating Gli2 Mol. Cell Biochem. 2014 397 277 283 25156120 10.1007/s11010-014-2195-z Sun, Z. et al. miR-202 suppresses proliferation and induces apoptosis of osteosarcoma cells by downregulating Gli2. Mol. Cell Biochem. 397 , 277–283 (2014). 25156120 10.1007/s11010-014-2195-z

553. Zhang J miRNA-218 regulates the proliferation and apoptosis of cervical cancer cells via targeting Gli3 Exp. Ther. Med. 2018 16 2433 2441 30210595 10.3892/etm.2018.6491 PMC6122525 Zhang, J. et al. miRNA-218 regulates the proliferation and apoptosis of cervical cancer cells via targeting Gli3. Exp. Ther. Med. 16 , 2433–2441 (2018). 30210595 10.3892/etm.2018.6491 PMC6122525

554. Guan B MicroRNA-218 inhibits the migration, epithelial-mesenchymal transition and cancer stem cell properties of prostate cancer cells Oncol. Lett. 2018 16 1821 1826 30008871 10.3892/ol.2018.8877 PMC6036488 Guan, B. et al. MicroRNA-218 inhibits the migration, epithelial-mesenchymal transition and cancer stem cell properties of prostate cancer cells. Oncol. Lett. 16 , 1821–1826 (2018). 30008871 10.3892/ol.2018.8877 PMC6036488

555. Song J Novel long noncoding RNA miR205HG functions as an esophageal tumor-suppressive hedgehog inhibitor Cancers (Basel) 2021 13 1707 33916875 10.3390/cancers13071707 PMC8038513 Song, J. et al. Novel long noncoding RNA miR205HG functions as an esophageal tumor-suppressive hedgehog inhibitor. Cancers (Basel) 13 , 1707 (2021). 33916875 10.3390/cancers13071707 PMC8038513

556. Du W Li D Xie J Tang P miR‑367‑3p downregulates Rab23 expression and inhibits hedgehog signaling resulting in the inhibition of the proliferation, migration, and invasion of prostate cancer cells Oncol. Rep. 2021 46 192 34278506 10.3892/or.2021.8143 PMC8299014 Du, W., Li, D., Xie, J. & Tang, P. miR‑367‑3p downregulates Rab23 expression and inhibits hedgehog signaling resulting in the inhibition of the proliferation, migration, and invasion of prostate cancer cells. Oncol. Rep. 46 , 192 (2021). 34278506 10.3892/or.2021.8143 PMC8299014

557. Zhao D Cui Z MicroRNA-361-3p regulates retinoblastoma cell proliferation and stemness by targeting hedgehog signaling Exp. Ther. Med. 2019 17 1154 1162 30679988 10.3892/etm.2018.7062 PMC6327618 Zhao, D. & Cui, Z. MicroRNA-361-3p regulates retinoblastoma cell proliferation and stemness by targeting hedgehog signaling. Exp. Ther. Med. 17 , 1154–1162 (2019). 30679988 10.3892/etm.2018.7062 PMC6327618

558. Zhang H The expression of microRNA-324-3p as a tumor suppressor in nasopharyngeal carcinoma and its clinical significance Onco Targets Ther. 2017 10 4935 4943 29066913 10.2147/OTT.S144223 PMC5644595 Zhang, H. et al. The expression of microRNA-324-3p as a tumor suppressor in nasopharyngeal carcinoma and its clinical significance. Onco Targets Ther. 10 , 4935–4943 (2017). 29066913 10.2147/OTT.S144223 PMC5644595

559. Xu H MiR-324-5p inhibits proliferation of glioma by target regulation of GLI1 Eur. Rev. Med. Pharmacol. Sci. 2014 18 828 832 24706306 Xu, H. et al. MiR-324-5p inhibits proliferation of glioma by target regulation of GLI1. Eur. Rev. Med. Pharmacol. Sci. 18 , 828–832 (2014). 24706306

560. Tang B MicroRNA-324-5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling Int. J. Cancer 2018 142 109 120 28905994 10.1002/ijc.31041 Tang, B. et al. MicroRNA-324-5p regulates stemness, pathogenesis and sensitivity to bortezomib in multiple myeloma cells by targeting hedgehog signaling. Int. J. Cancer 142 , 109–120 (2018). 28905994 10.1002/ijc.31041

561. Du W Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness Neuro Oncol. 2015 17 243 253 25173582 10.1093/neuonc/nou217 PMC4288524 Du, W. et al. Targeting the SMO oncogene by miR-326 inhibits glioma biological behaviors and stemness. Neuro Oncol. 17 , 243–253 (2015). 25173582 10.1093/neuonc/nou217 PMC4288524

562. Huang J Xu Y Lin F The inhibition of microRNA-326 by SP1/HDAC1 contributes to proliferation and metastasis of osteosarcoma through promoting SMO expression J. Cell Mol. Med. 2020 24 10876 10888 32743904 10.1111/jcmm.15716 PMC7521251 Huang, J., Xu, Y. & Lin, F. The inhibition of microRNA-326 by SP1/HDAC1 contributes to proliferation and metastasis of osteosarcoma through promoting SMO expression. J. Cell Mol. Med. 24 , 10876–10888 (2020). 32743904 10.1111/jcmm.15716 PMC7521251

563. Xue Q MicroRNA-338-3p inhibits colorectal carcinoma cell invasion and migration by targeting smoothened Jpn. J. Clin. Oncol. 2014 44 13 21 24277750 10.1093/jjco/hyt181 Xue, Q. et al. MicroRNA-338-3p inhibits colorectal carcinoma cell invasion and migration by targeting smoothened. Jpn. J. Clin. Oncol. 44 , 13–21 (2014). 24277750 10.1093/jjco/hyt181

564. Xiong Z Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO Aging (Albany NY) 2019 11 12345 12360 31895689 10.18632/aging.102576 PMC6949074 Xiong, Z. et al. Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO. Aging (Albany NY) 11 , 12345–12360 (2019). 31895689 10.18632/aging.102576 PMC6949074

565. Liu Y Downregulation of MiR-431 expression associated with lymph node metastasis and promotes cell invasion in papillary thyroid carcinoma Cancer Biomark. 2018 22 727 732 29945344 10.3233/CBM-181253 PMC13078490 Liu, Y. et al. Downregulation of MiR-431 expression associated with lymph node metastasis and promotes cell invasion in papillary thyroid carcinoma. Cancer Biomark. 22 , 727–732 (2018). 29945344 10.3233/CBM-181253 PMC13078490

566. Wen S miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer Oncogene 2015 34 717 725 24608427 10.1038/onc.2014.9 Wen, S. et al. miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene 34 , 717–725 (2015). 24608427 10.1038/onc.2014.9

567. Wang T Feng J Zhang A miR-584 inhibits cell proliferation, migration and invasion in vitro and enhances the sensitivity to cisplatin in human cervical cancer by negatively targeting GLI1 Exp. Ther. Med. 2020 19 2059 2066 32104266 10.3892/etm.2020.8449 PMC7027228 Wang, T., Feng, J. & Zhang, A. miR-584 inhibits cell proliferation, migration and invasion in vitro and enhances the sensitivity to cisplatin in human cervical cancer by negatively targeting GLI1. Exp. Ther. Med. 19 , 2059–2066 (2020). 32104266 10.3892/etm.2020.8449 PMC7027228

568. Feng J Wang T MicroRNA-873 serves a critical role in human cervical cancer proliferation and metastasis via regulating glioma-associated oncogene homolog 1 Exp. Ther. Med. 2020 19 1243 1250 32010295 10.3892/etm.2019.8348 PMC6966164 Feng, J. & Wang, T. MicroRNA-873 serves a critical role in human cervical cancer proliferation and metastasis via regulating glioma-associated oncogene homolog 1. Exp. Ther. Med. 19 , 1243–1250 (2020). 32010295 10.3892/etm.2019.8348 PMC6966164

569. Cao D Yu T Ou X MiR-873-5P controls gastric cancer progression by targeting hedgehog-GLI signaling Pharmazie 2016 71 603 606 29441930 10.1691/ph.2016.6618 Cao, D., Yu, T. & Ou, X. MiR-873-5P controls gastric cancer progression by targeting hedgehog-GLI signaling. Pharmazie 71 , 603–606 (2016). 29441930 10.1691/ph.2016.6618

570. Xu Z Huang C Hao D MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated hedgehog signaling pathway Oncol. Rep. 2017 37 1261 1269 27959416 10.3892/or.2016.5304 Xu, Z., Huang, C. & Hao, D. MicroRNA-1271 inhibits proliferation and promotes apoptosis of multiple myeloma cells through inhibiting smoothened-mediated hedgehog signaling pathway. Oncol. Rep. 37 , 1261–1269 (2017). 27959416 10.3892/or.2016.5304