The role of lncRNA NEAT1 in human cancer chemoresistance.

Introduction

Cancer, as the second leading cause of death in the world, is a serious threat to human health and has become a major public health problem worldwide [ 1 ]. The treatment of cancer mainly includes surgical treatment, endocrine therapy, targeted therapy, immunotherapy, radiotherapy and chemotherapy [ 2 ]. Chemotherapy is one of the most effective means of clinical treatment of cancer at present. It can significantly reduce the risk of long-term recurrence of cancer and improve the overall survival and quality of life of patients. It has become the main treatment method for patients with systemic cancer, patients with advanced cancer without surgical indications and patients with recurrent and metastatic cancer [ 3 – 5 ]. However, with the continuous use of chemotherapy drugs, some patients will develop resistance to chemotherapy drugs, resulting in poor chemotherapy effect and poor prognosis, which has become a very difficult scientific problem in the field of cancer chemotherapy. Clinical data show that more than 70% of ovarian cancer patients relapse after receiving continuous chemotherapy for 12–18 months due to drug resistance to chemotherapeutic drugs, and the 5-year survival rate is less than 50% [ 6 ]. Therefore, it is undoubtedly an effective measure to solve the problem of clinical cancer chemotherapy resistance and poor prognosis by clarifying the molecular mechanism of driving cancer to produce chemotherapy resistance, deeply analyzing and finding potential new targets for cancer chemotherapy sensitization.

Chemotherapy induced drug resistance can be regarded as an adaptive change of cancer cells to chemotherapeutic drugs [ 7 ]. Cancer cells are resistant to chemotherapeutic drugs by altering cell cycle checkpoints, drug transport and metabolism, DNA damage repair, apoptosis, EMT, autophagy, cancer stem cell properties, and metabolic reprogramming [ 8 – 10 ]. Therefore, exploring the important regulatory factors that regulate the biological behavior of cancer cells to produce drug resistance and their mechanism of action is an urgent need to find potential new targets for chemotherapy sensitization and solve clinical cancer chemotherapy resistance. Recent studies have shown that long non-coding RNA (LncRNA) can affect the chemotherapy resistance of cancer by inhibiting apoptosis, promoting DNA damage repair and changing drug metabolism, and plays an important regulatory role in cancer chemotherapy resistance [ 11 , 12 ]. LncRNAs are a class of non-coding RNA molecules with a length of more than 200 nucleotides that are transcribed from different regions of the genome by RNA polymerase II. They are widely present in cells and play an important role in various biological processes such as development, metabolism, immunity, and cancer [ 13 ]. Although LncRNA does not encode proteins, it can affect gene expression through chromatin remodeling, transcriptional regulation, splicing regulation, translation regulation, miRNA sponge and other mechanisms [ 14 ]. According to their different structures and characteristics, lncRNAs can be divided into: intron lncRNA, bidirectional lncRNA, intergenic lncRNA, enhancer lncRNA, sense lncRNA, antisense lncRNA, promoter lncRNA, and small nucleolar RNA terminal lncRNA [ 15 – 20 ]. LncRNAs typically have complex secondary structures, such as single-stranded, double-stranded, and circular. They act as decoy molecule, guide molecule, signal molecule, and scaffold molecule to interact with DNA, RNA, and proteins, respectively, thereby regulating the occurrence and development of cancer [ 20 ](Fig. 1 ). More and more evidence suggests that lncRNA plays a complex and multifaceted role in chemotherapy resistance. It can affect chemotherapy resistance by inhibiting apoptosis, promoting cancer stem cell characteristics, affecting cell metabolism, inducing autophagy, affecting cell cycle regulation, reshaping DNA repair capacity, and changing drug metabolism and transport [ 21 ]. Jiang et al. [ 22 ]. found that the lncRNA DDIT4-AS1 could promote paclitaxel resistance in triple-negative breast cancer by recruiting the RNA-binding protein AUF1 to stabilize DDIT4 mRNA and enhance the interaction between DDIT4 and AUF1, thereby inducing autophagy. MEIS1 is a member of the TALE family and enhances cancer sensitivity to oxaliplatin by preventing DNA damage repair. LncRNA ELFN1-AS1 promotes DNA methylation and H3K27me3 in the promoter region of MEIS1 by guiding EZH2-DNMT3 a to locate in the promoter region of MEIS1, inhibits the transcription of MEIS1, and thus promotes oxaliplatin resistance in colorectal cancer by preventing DNA damage repair [ 23 ]. Long non-coding RNA nuclear paraspeckle assembly transcript 1(LncRNA NEAT1) is a highly conserved intergenic LncRNA, which was first discovered in mammalian genome-wide screening [ 24 ]. Studies have shown that NEAT1 is associated with the development of a variety of human diseases, including non-cancerous lesions such as sepsis and neurodegenerative lesions, as well as a variety of cancers such as hepatocellular carcinoma [ 25 – 27 ]. NEAT1 has different expression patterns in different cancers and can affect the occurrence, development and metastasis of many cancers by acting as oncogenes or oncogenes, and is a potential diagnostic and therapeutic target for cancer [ 24 ]. Recent studies have shown that NEAT1 is closely associated with chemoresistance in a variety of cancers, and can regulate the sensitivity of cancers such as myeloma and glioblastoma to chemotherapeutic agents through multiple pathways and pleiotropic effects, thus affecting the efficacy of cancer chemotherapy [ 28 – 30 ]. Therefore, in-depth study of the specific molecular regulation mechanism of NEAT1 in cancer chemotherapy resistance is of great value for screening effective and potential new targets for cancer chemotherapy sensitization, and provides new ideas and new directions for cancer chemotherapy.

Fig. 1 The function of lncRNA. ( a ) decoy molecule. ( b ) guide molecule. ( c ) signal molecule. ( d ) scaffold molecule

Based on the main molecular mechanism of cancer chemotherapy resistance, this paper systematically expounds the molecular regulation and function of lncRNA NEAT1 in cancer chemotherapy resistance, which provides a scientific basis for the development of NEAT1 as a new target for cancer chemotherapy sensitization, and provides new ideas and insights for solving the problem of cancer chemotherapy resistance.

The biogenesis and function of NEAT1

NEAT1 is located in the 11q13.1 region of human chromosome and interacts with RNA binding proteins to form important structural scaffolds of para-spots [ 31 ]. NEAT1 has two transcript variants with the same transcription start site, namely the short variant NEAT1-1 (MENε, 3.7 kb) and the long variant NEAT1-2 (MENβ, 22.7 kb) [ 32 ]. NEAT1-2 is the basic structural component of the paraspot, and the middle domain contains multiple sites that can bind to the paraspot proteins SFPQ, NONO, PSPC1 and FUS. These binding sites are necessary and sufficient for the formation, stability and integrity of the paraspot (Fig. 2 ) [ 33 ].

Fig. 2 Biogenesis of NEAT1. ( A ) Location of NEAT1-1 and NEAT1-2 at the MEN site. ( B ) paraspeckle proteins(PSP) participates in the synthesis of a single NEAT1-2 ribonucleoprotein complex and a paraspeckle model

At present, NEAT1 has been shown to be able to regulate biological functions of cancer cells by interacting with mRNA, DNA and proteins (Figure 3 ). For example (1) Regulate target gene transcription. In melanoma, NEAT1 binds to BRD4 through the BET domain, blocking WDR5 in a non active form, thereby mediating inhibitory effects on downstream target genes of BRD4 [ 34 ]; (2) Mediating epigenetic modification. NEAT1 mediates the trimethylation of histone H3 lysine 27 in the promoter region of target-specific genes Axin2 and GSK3B by acting as a scaffold and recruiting chromosome modification enzyme EZH2 to promote the nuclear transport of β-catenin, thereby promoting the growth and invasion of glioblastoma [ 35 ]. Similarly, NEAT1 directly interacts with BRG1 and significantly inhibits the expression of GADD45A by enhancing local H3K27me3 modification and reducing H3K4me3 modification, ultimately promoting the proliferation and inducing apoptosis of gastric cancer cells [ 36 ]; (3) Regulating protein activity. The hairpin A of NEAT1 can interact with the M1 domain of PGK1, prevent the degradation of PGK1 protein by inhibiting ubiquitination, and promote the expression of PGK1 protein to enhance the proliferation and glycolysis of glioma cells [ 37 ]; (4) Regulate the stability of mRNA. NEAT1 can recruit hnRNPA2B1 to bind to RPRD1B to promote the stability of RPRD1B mRNA, thereby promoting the metabolism of fatty acids and lymph node metastasis in gastric cancer [ 38 ]; (5) Sponge miRNA. NEAT1 acts as a competitive endogenous RNA (ceRNA) to regulate the transcription of target genes [ 39 , 40 ]. NEAT1 competitively binds to miR-146b-5p to attenuate the inhibitory effect of miR-146b-5p on TRAF6, thereby increasing the expression of TRAF6 and promoting the proliferation, migration and invasion of pancreatic cancer cells [ 41 ]. In addition, NEAT1 can target miR-152-3p to up-regulate the expression of CDK19 and promote the cell viability, cycle and apoptosis of ovarian cancer cells, which can be reversed by evodiamine [ 42 ]. Therefore, the regulation of NEAT1 on cancer chemotherapy resistance may be achieved through these pathways.

Fig. 3 Mechanisms of NEAT1 in cancer. ( a ) Mediating epigenetic modification. ( b ) Regulating protein activity. ( c ) Regulate target gene transcription. ( d ) Regulate the stability of mRNA. ( e ) Sponge miRNA. ( f ) NEAT1 participates in the biological processes of cancer

Expression and clinical characterization of NEAT1 in different cancers

With the development of genome-wide analysis technology, lncRNAs have been proposed as biomarkers for early detection and prognosis of various cancers [ 43 , 44 ]. NEAT1 is dysregulated in a wide range of cancers and is significantly associated with complex clinicopathological features. A number of studies have shown that NEAT1 affects various clinicopathological features such as TMN stage, tumor size, lymph node metastasis, and distant metastasis in cancer patients. Most cancer patients with high NEAT1 expression often indicate poor prognosis and shorter survival (Table 1 ). Therefore, the dysregulation of NEAT1 can be regarded as a robust and credible adverse prognostic factor in human cancer, which will help to develop effective strategies for the diagnosis, treatment and prognosis of cancer in the future.

Table 1 Clinical characteristics of NEAT1 in diverse cancer Cancer type Expression Numbers of clinical samples Clinical characteristics Ref. clinical stage metastasis survival Prostate cancer upregulation 130 paired tissue specimens of PC patients and matched normal prostate tissue TNM III-IV↑ lymph node metastasis, distant metastasis overall survival↓ [ 45 ] Colorectal cancer upregulation serum samples from 406 CRC patients and healthy subjects TNM III-IV↑ distant metastasis overall survival↓ [ 46 ] upregulation tissue and serum samples from 271 CRC patients and healthy subjects tumor extent↑ distant metastasis NA [ 47 ] Breast cancer upregulation serum samples from 178 patients with BC, benign breast diseases and healthy subjects TNM II-IV↑ NA NA [ 48 ] Oral squamous cell carcinoma downregulation 34 pairs of OSCC tissues and adjacent non cancerous matching tissues samples NA NA overall survival↓ [ 49 ] Nasopharyngeal carcinoma upregulation 128 specimens of NPC tissue and nasopharyngeal epithelial tissue TNM III-IV↑ distant metastasis overall survival↓ [ 50 ] Multiple myeloma upregulation bone marrow samples from 144 MM patients and healthy subjects ISS stage↑ NA overall survival↓ [ 51 ] upregulation bone marrow and blood samples from 81 MM patients and healthy subjects ISS stage↑ NA progression-free survival ↓ [ 28 ] Laryngeal squamous cell carcinoma upregulation tissue samples from 102 LSCC patients TNM III-IV↑ lymph node metastasis overall survival↓ [ 52 ]

The molecular mechanism of NEAT1 in human cancer chemotherapy resistance

The role of NEAT1 in chemotherapy resistance of human cancer involves a variety of mechanisms, including inhibition of apoptotic pathways, increased ATP-driven drug efflux, enhanced DNA damage repair, and induction of autophagy (Table 2 ; Fig. 4 ).

Table 2 The mechanism of NEAT1 mediated chemotherapy resistance Cancer type Related drugs Expression Effect Related genes and pathways Ref. Non-small cell lung cancer paclitaxel upregulation apoptosis AKT/mTOR [ 53 ] paclitaxel upregulation apoptosis AKT [ 54 ] cisplatin upregulation cellular stemness β-catenin, GSK3β, CD133, CD44, SOX2, Nanog, OCT4 [ 55 ] Breast cancer paclitaxel upregulation cell cycle miR-133b, CXCL12 [ 56 ] 5-Fu upregulation EMT miR-211, HMGA2 [ 57 ] Bladder cancer cisplatin upregulation apoptosis c-MYC, OCT4, p53 [ 58 ] Ovarian cancer cisplatin upregulation apoptosis miR-770-5p, PAPR1 [ 59 ] Neuroblastoma cisplatin upregulation apoptosis miR-326 [ 60 ] Hepatocellular carcinoma sorafenib upregulation autophagy miR-204, ATG3 [ 61 ] 5-Fu upregulation drug transport P-gp, MRP1 [ 62 ] Lymphoblastic leukemia multidrug resistance upregulation drug transport miR-335-3p, ABCA3 [ 63 ] Colorectal cancer 5-Fu upregulation autophagy miR-34a, HMGB1 [ 64 ] 5-Fu upregulation cellular stemness ALDH1, c-Myc, H3K27ac, SOX2, Nanog, OCT4 [ 65 ] Osteosarcoma cisplatin upregulation cell cycle miR-34c, CCND1, CDK4 [ 66 ] bleomycin upregulation DNA repair γ-H2A.X [ 67 ] Prostatic cancer docetaxel upregulation drug transport miR-34a-5p, miR-204-5p, ACSL4, MRP4, BCRP [ 68 ] Endometrial cancer paclitaxel upregulation drug transport miR-98, MRP-7, PLAUR [ 69 ] Multiple myeloma bortezomib upregulation apoptosis miR-29b-3p, SP1 [ 70 ] Bortezomib carfilzomib upregulation DNA repair RPA32 [ 71 ] Pancreatic cancer gemcitabine upregulation EMT miR-491-5p, Snail, SOCS3 [ 72 ] gemcitabine upregulation EMT miR-506-3p, ZEB2 [ 73 ] Cervical cancer 5-Fu upregulation glycolysis miR-34a, LDHA [ 74 ]

NEAT1 inhibits cell apoptosis

Apoptosis is a gene-controlled, autonomous and orderly death process that is used to maintain the stability of the internal environment, and the escape of cancer cells from apoptosis is considered to be one of the hallmarks of cancer [ 75 ]. During chemotherapy, the DNA of cancer cells will be subjected to irreparable chemical damage, thereby inducing apoptosis. However, cancer cells will take a variety of ways to escape apoptosis, including inhibiting pro-apoptotic signals, inducing anti-apoptotic signals, or affecting apoptotic signal transduction pathways through gene mutations. The combined effects of these mechanisms promote the development of chemotherapy resistance in cancer cells [ 76 , 77 ]. The apoptosis pathway mainly includes mitochondrial pathway and death receptor pathway. When the mitochondrial apoptotic pathway is activated, BAX is relocated to the mitochondrial outer membrane and forms an oligomeric complex with BAK1. The complex is inserted into the outer membrane pores of the mitochondria, causing changes in mitochondrial osmotic pressure and loss of transmembrane potential, prompting the release of cytochrome c from the mitochondria to the cytoplasm. Cytochrome c entering the cytoplasm binds to Apaf1 to form an apoptotic complex, which recruits and activates the precursor of cysteine aspartic protease-9 (caspase-9), thereby activating Caspase-3 and Caspase-7, triggering the Caspase cascade and ultimately leading to apoptosis [ 78 ]. NEAT1 can inhibit apoptosis and promote chemotherapy resistance of cancer by regulating the expression of key apoptosis-related factors in the mitochondrial apoptosis pathway. In non-small cell lung cancer (NSCLC), NEAT1 can inhibit apoptosis and induce paclitaxel resistance in NSCLC cells by inhibiting the expression of apoptosis-related proteins cleaved caspase3 and cleaved PARP and activating the AKT/mTOR signaling pathway [ 53 , 54 ]. In ovarian cancer (OC) cells, NEAT1 up-regulates the expression of PARP1 and inhibits the expression of apoptosis-related proteins BAX and c-caspase3 by targeting miR-770-5p, thereby inhibiting apoptosis and inducing cisplatin resistance in OC cells [ 59 ]. Yang et al. [ 60 ] found that high expression of NEAT1 can inhibit the apoptosis of neuroblastoma (NB) cells and promote the resistance of NB cells to cisplatin by targeting down-regulating the expression level of miR-326 and inhibiting the expression of pro-apoptotic protein Bax. Multiple myeloma (MM) is a malignant tumor with abnormal proliferation of plasma cells in bone marrow. It has been found that high expression of NEAT1 in MM serum samples and cells can promote the chemoresistance of MM cells. The specific mechanism is that NEAT1 can up-regulate the expression of SP1 and down-regulate the expression of apoptosis-related proteins c-PARP and c-caspase3 through sponge miR-29b-3p, thereby inhibiting the apoptosis of MM cells and enhancing the tolerance of MM cells to bortezomib [ 70 ]. The cisplatin resistance of bladder cancer (BC) cells is also related to the regulation of NEAT1 on apoptosis escape. In cisplatin-resistant BC cells, up-regulated oncogene transcription factors c-MYC, OCT4 and p53 can be enriched in the NEAT1 promoter region and activate its transcription, inhibit apoptosis, and promote cisplatin resistance in BC cells [ 58 ].

NEAT1 promotes cell cycle progression

Uncontrolled cell proliferation caused by cell cycle disorders is an important feature of cancer [ 79 ]. The abnormal changes of proteins, enzymes, cytokines and cell cycle signaling pathways involved in cell cycle regulation are closely related to the occurrence, development and chemotherapy resistance of cancer [ 80 ]. NEAT1 can induce chemotherapy resistance by promoting the cell cycle progression of cancer cells. The G0/G1 phase of the cell cycle is an important period for cell volume growth and preparation for DNA replication and synthesis. NEAT1 can affect the chemoresistance of cancer cells by regulating the GO/G1 phase of the cell cycle. NEAT1 derived from BC paclitaxel-resistant SKBR-3/PR cell exosomes can induce paclitaxel resistance by regulating the GO/G1 phase of the cell cycle.CXCL12 plays an important regulatory role in promoting cancer chemotherapy resistance. In BC paclitaxel-resistant SKBR-3/PR cells, knockdown of NEAT1 can up-regulate the expression of miR-133b and down-regulate the expression of downstream CXCL12 protein, which promotes cell cycle arrest in G0/G1 phase and promotes the sensitivity of SKBR-3/PR cells to paclitaxel [ 56 ]. NEAT1 in osteosarcoma (OS) cells can also enhance the resistance of OS cells to cisplatin by promoting the G0/G1 phase of the cell cycle [ 66 ].

NEAT1 affects drug efflux

The reduction of intracellular accumulation of chemotherapeutic drugs is one of the main causes of cancer drug resistance, which is closely related to the drug efflux system [ 81 ]. Adenosine triphosphate binding cassette (ABC) transporters in the drug efflux system can regulate the absorption, distribution and clearance of drugs. Its family members, multidrug resistance protein 1 (ABCB1/MDR1/P-gp) and multidrug resistance-associated protein 1 (ABCC1/MRP1), can transport chemotherapeutic drugs with different structures and functions from intracellular to extracellular by using the energy hydrolyzed by ATP, significantly reducing intracellular drug concentration and playing an important role in the development of cancer chemoresistance [ 82 , 83 ]. NEAT1 can promote the efflux of chemotherapeutic drugs by regulating the expression and activity of ABC transporters in cancer cells, thereby causing cancer chemotherapy resistance. MRP subfamily members of ABC transporters are expressed in a variety of cancers as major players in cancer multidrug resistance. Huang et al. [ 69 ]. found that multidrug resistance protein 7 (MRP7), which is highly expressed in paclitaxel-resistant endometrial cancer (EC) cells, can promote the paclitaxel resistance of EC cells, while NEAT1 can up-regulate the expression level of MRP7 through sponge miR-98, thereby further enhancing the paclitaxel resistance of EC cells. ACSL4 has been shown to enhance chemoresistance of cancer cells by affecting the expression of ABC transporters [ 84 ]. The expression of NEAT1 is significantly up-regulated in prostate cancer (PCa) tissues and cells, and promotes the resistance of PCa cells to docetaxel. The specific mechanism is that NEAT1, as a ceRNA, up-regulates the expression of ACSL4 by sponge miR-34a-5p or miR-204-5p, and promotes the high expression of downstream ABC transporters MRP4 and BCRP, thereby enhancing the resistance of PCa cells to docetaxel [ 68 ]. BCLAF is a multifunctional BCL2-related transcription factor that is up-regulated in hepatocellular carcinoma (HCC). It enhances the transcription of NEAT1 by targeted binding to the promoter region of NEAT1, and further promotes the expression levels of MRP1 and P-gp to induce 5-Fu resistance in HCC cells [ 62 ]. ABCA3 is a member of the ABC1 subfamily and is up-regulated in the multidrug-resistant group of childhood acute lymphoblastic leukemia. It is a new tumor prognostic marker. NEAT1 can target up-regulate the expression of ABCA3 through sponge miR-335-3p, and ultimately lead to chemotherapy resistance in children with acute lymphoblastic leukemia [ 63 ].

NEAT1 promotes DNA damage repair

The mechanism of DNA repair is triggered after DNA damage, and failure to repair DNA properly is a major cause of genetic mutations and oncogene activation. Chemotherapy drugs usually work by inducing DNA damage in cancer cells, and cancer cells can reduce the effect of chemotherapy by enhancing DNA damage repair [ 85 ]. DNA damage is mainly repaired by five pathways: homologous recombination (HR), nucleotide excision repair (NER), non-homologous end joining (NHEJ), base excision repair (BER) and mismatch repair (MMR) [ 86 ]. NEAT1 promotes chemotherapeutic resistance in cancer mainly by enhancing the homologous recombination ability of cancer cells. In MM cells, NEAT1 enhances the DNA damage repair process by upregulating the expression of RPA32, a key molecule in the HR pathway, thus promoting cell resistance to bortezomib and carfezomib. However, silencing NEAT1 can reduce the expression of RPA32, induce a large amount of DNA damage, and enhance the sensitivity of MM cells to bortezomib and carfilzomib [ 71 ]. Recent studies have shown that NEAT1 is positively correlated with the HR-related proteins RAD51 and FOXM1 in OC, and that knockdown of NEAT1 sensitizes cancer cells to platinum-based chemotherapeutic agents by inhibiting the HR process [ 87 ]. In addition, NEAT1 can also reduce the number of DNA damage lesions by promoting the expression of HRR related protein ATR, thereby promoting the resistance of OS cells to bleomycin [ 67 ].

NEAT1 enhances EMT

EMT gives cancer cells the ability to invade and metastasize, which is an important factor in promoting cancer progression and causing chemotherapy failure [ 88 ]. During chemotherapy, cancer cells that have undergone EMT gain the ability to resist apoptosis, and this resistance often leads to increased tolerance of cancer cells to chemotherapy. NEAT1 can promote chemotherapy resistance of cancer cells by regulating the EMT process. SOCS3 is a cytokine-induced protein that can inhibit the development of cancer by regulating cell proliferation and drug resistance [ 89 ]. In pancreatic cancer (PC) cells, NEAT1 can enhance the resistance of PC cells to gemcitabine by promoting EMT process. The specific mechanism is that NEAT1 inhibits downstream SOCS3 expression through sponge miR-491-5p targeting. Thus, the expression of EMT-related proteins E-cadherin is down-regulated, Snail, vimentin and fibronectin are up-regulated, and the resistance of PC cells to gemcitabine is enhanced [ 72 ]. Similarly, NEAT1 can also up-regulate the expression of transcription regulator ZEB2 in PC cells by targeting sponge miR-506-3p, to promote the EMT process of cells and induce cell resistance to gemcitabine [ 73 ]. In BC, high expression of NEAT1 is associated with invasive breast cancer phenotype and poor patient prognosis. HMGA2 is one of the members of the high mobility group protein superfamily with the HMG domain. It is a non-histone protein that can bind DNA and modify chromatin conformation to regulate gene expression. HMGA2 is closely related to tumor formation, and abnormally expressions in various cancer tissues, which can promote the invasion and migration of BC cells [ 90 ]. Down-regulation of NEAT1 inhibited the EMT process and increased the sensitivity of BC cells to 5-Fu by targeting the miR-211/HMGA2 axis [ 57 ].

NEAT1 induces autophagy

Autophagy, also known as type II programmed cell death, degrades damaged proteins and dysfunctional organelles through autophagolysosomes, providing cells with energy and nutrition to maintain cell homeostasis [ 91 ]. Autophagy is a double-edged sword in cancer, in the early stage of cancer development, Autophagy can eliminate damaged cells to play a role in cancer suppression. However, in the later stages of cancer progression, autophagy acts as a cancer protective factor. Under the stimulation of chemotherapy drugs, cancer cells accelerate drug decomposition by increasing their autophagy level, thus improving the tolerance of cancer cells to chemotherapy drugs [ 92 , 93 ]. NEAT1 can enhance chemotherapy resistance of cancer cells by inducing autophagy. In colorectal cancer (CRC) tissues and cells, high expression of NEAT1 promotes resistance to 5-Fu in CRC cells by inducing autophagy. HMGB1 is a member of the high mobility group protein superfamily, which has been shown to promote the resistance of cancer to radiotherapy and chemotherapy [ 94 ]. Knockdown of NEAT1 can target down-regulate the expression of miR-34a and up-regulate the expression of HMGB1, thereby inhibiting the expression of autophagy related proteins Bclin-1 and ULK1 and the ratio of LC3II/I, and enhancing the sensitivity of CRC cells to 5-Fu [ 64 ]. NEAT1 can also promote the expression of downstream ATG3 through sponge miR-204, induce autophagy in HCC cells, and promote the resistance of HCC cells to sorafenib [ 61 ].

NEAT1 enhances cancer stem cell properties

Cancer stem cells (CSCs) are a group of cancer cells with the ability of self-renewal and differentiation, which are closely related to cancer metastasis, recurrence and chemotherapy resistance [ 95 , 96 ]. After chemotherapy, CSCs in cancer tissues protect themselves from the destructive effects of chemotherapeutic drugs and enhance their resistance to chemotherapeutic drugs through many ways like scavenging reactive oxygen species, inducing cell dormancy and activating developmental signaling pathways [ 97 ]. Cancer stemness transcription factors such as SOX2, OCT4, and Nanog serve as markers for CSCs, which can maintain the multipotency and self-renewal of CSCs through various pathways such as promoting the EMT process, modulating the signaling pathway, and regulating the cell cycle [ 98 ]. NEAT1 can induce chemoresistance in cancer cells by regulating the expression of these stemness factors. In CRC tissues and cells, high expression of NEAT1 is associated with short recurrence-free survival in CRC patients. NEAT1 is able to act as a scaffold to affect chromatin remodeling in cancer cells, increase the expression of H3K27ac and lead to increased levels of acetylation in the ALDH1 and c-Myc promoter regions, which in turn upregulates the expression of the cancer stemness factors SOX2, Nanog, and OCT4, and enhances the stemness of colorectal cancer cells and increases their resistance to 5-Fu [ 65 ]. NEAT1 can also affect CSCs by activating the signaling pathway to induce chemoresistance of cancer cells. The specific mechanism is that NEAT1 promotes the sphere-forming ability of A549/CDDP cells by activating the Wnt/β-catenin signaling pathway, increases the expression levels of CSCs-related stemness factors CD133, CD44, SOX2, Nanog, OCT4, induces the stemness of A549/CDDP cells, and further enhances its resistance to cisplatin [ 55 ].

NEAT1 promotes aerobic glycolysis

Cancer cells have different metabolic patterns from normal cells. Even under aerobic conditions, rapidly proliferating cancer cells tend to consume glucose to produce lactic acid, which is called Warburg effect or aerobic glycolysis [ 99 ]. A key mechanism of chemotherapeutic resistance is the metabolic reprogramming of cancer, which involves changes in cellular metabolic pathways, including increased aerobic glycolysis, to provide cancer cells with the necessary energy to escape the effects of chemotherapy [ 100 , 101 ]. NEAT1 can affect the chemotherapy resistance of cancer by promoting aerobic glycolysis. LDHA as a key enzyme in the glycolysis process, plays an important role in promoting the growth of cancer cells [ 102 ]. In cervical cancer (CCA), NEAT1 targets and upregulates LDHA expression via sponge miR-34a, which promotes the cellular glycolysis rate and enhances 5-Fu resistance in CCA cells [ 74 ].

Fig. 4 The mechanism of NEAT1 mediated cancer chemotherapy resistance

Conclusion and future perspectives

As an important means of cancer treatment, chemotherapy has a significant effect on improving the quality of life and prognosis of patients. However, the emergence of chemotherapy resistance is an important cause of clinical chemotherapy failure. At present, lncRNA has been shown to play an important regulatory role in a variety of life activities, especially in the regulation of chemotherapy resistance of cancer cells. LncRNA can regulate the chemotherapy resistance of cancer cells through a variety of ways, and can be used as a potential sensitization target to improve the efficacy of chemotherapy. NEAT1 is one of the most widely studied lncRNAs, and it is also the most up-regulated lncRNA in the pan-cancer genome data set, which plays an important regulatory role in tumorigenesis and development. Studies have shown that NEAT1 is closely related to the malignant biological behavior of many cancers and the poor prognosis of patients, and is a potential cancer therapeutic target. In this review, we explore the different mechanisms by which NEAT1 induces drug resistance in a variety of tumors. The results showed that NEAT1 could cause resistance to a variety of chemotherapeutic agents, such as paclitaxel, cisplatin, bortezomib, 5-FU, bleomycin, and so on. NEAT1 can regulate the resistance of cancer cells to chemotherapeutic drugs by inhibiting apoptosis, inducing autophagy, promoting EMT, enhancing the characteristics of cancer stem cells, and promoting drug efflux. Therefore, NEAT1 may be a new potential therapeutic target for overcoming cancer chemotherapy resistance. Targeting NEAT1 can not only effectively anti-tumor, but also enhance the effect of chemotherapy, thus contributing to the comprehensive treatment of cancer and improving the prognosis of patients.

At present, new therapies targeting lncRNAs are a research hotspot in cancer treatment. Therapeutic strategies for functional lncRNA development, such as antisense oligonucleotides (antagomiRs/ASO), RNA nanotechnology, and CRISPR-Cas9 technology, have achieved certain results. Li et al. [ 103 ]. found that inhibition of NEAT1 expression by CRISPR-Cas9 technology can make anti-radiation cancer cells more sensitive to radiation, and reduce their cell proliferation and stem cell marker expression, indicating that CRISPR-Cas9 gene editing technology can be used to interfere with dysfunctional NEAT1 in cancer. The study of NEAT1-related ceRNA network can also open up new avenues for cancer treatment and overcoming drug resistance. NEAT1 competes with specific miRNAs. These competitive endogenous RNA networks form a complex and highly regulated mechanism to control gene expression and cell function, which provides new possibilities for targeting NEAT1 in combination with traditional chemotherapy to overcome cancer chemotherapy resistance.In addition, NEAT1 is secreted in almost all biological fluids, which allows it to be used as a biomarker for clinical diagnosis of cancer and development of chemotherapy resistance in cancer, and its expression level can differentiate between chemo-sensitive and chemo-resistant tumors, which can help in the early detection of chemo-resistance and timely change of therapeutic strategies.Some of the current studies have accurately identified inhibitors targeting NEAT1 and found their value in reversing tumor chemotherapy resistance, providing an important theoretical basis for clinical development of new anticancer drugs.

In recent years, many advances have been made in the study of the mechanism of action of NEAT1 in cancer development, but the study of the mechanism of action of NEAT1 in cancer chemotherapy resistance is still in its infancy. There are still a number of challenges that need to be addressed.First, the molecular mechanism of NEAT1 in cancer chemoresistance is a complex regulatory network, and although a large number of NEAT1-related signaling pathways have been found to be associated with cancer chemoresistance, there are still many unknown signaling pathways and potential molecular targets waiting to be further explored; Second, NEAT1 has the potential to become a biomarker and sensitization target for clinical cancer diagnosis and treatment, but more studies are needed to further validate whether its reliability and sensitivity are sufficient for clinical applications; Finally, although the currently discovered NEAT1-specific inhibitors have shown significant anti-cancer effects, due to the lack of basic research on the potential downstream pathways of NEAT1, there is a certain risk in gene therapy targeting NEAT1 compared with traditional drugs. Due to the lack of clinical data, the efficacy and safety of drugs targeting NEAT1 in humans is unknown, and unexpected side effects may occur when applied in the clinic. In addition, specific targeting methods and delivery systems need to be further improved to ensure that only NEAT1 is affected.

In summary, in-depth understanding and investigation of the specific role of NEAT1 in chemotherapy resistance in different cancers can help to reveal the intrinsic mechanism of cancer chemotherapy resistance, which is of great significance to the clinical research and development of targeted chemotherapy sensitizing drugs, and to improve the efficacy of chemotherapy and prognosis of cancer patients. This article describes the molecular mechanism of NEAT1 in cancer chemoresistance, and explores the possibility of NEAT1 as a target for cancer chemotherapy sensitization, in order to provide a theoretical basis from the perspective of lncRNA, find new targets for chemotherapy sensitization, and improve clinical chemotherapy efficacy.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Feng Long and Xue Li should be considered joint first author

Author contributions

F.L. wrote the manuscript and drew the figures. X.L. collected the related papers, created the Tables, and helped to revise the manuscript. Other authors designed and revised the manuscript. All the authors read and approved the final version of the review.

Funding

This work was financially supported by the National Key R and D Program of China (2018YFE0205100), Open Project of Dunhuang Key Laboratory of Medicine and Translational Education (DHYX22-10), “Double First-Class” Key Research Projects in Gansu Province (GSSYLXM-01),Flagship Education Projects (2021jyjbgs-03), Innovation Fund Program for Higher Education Teachers(2024 A-088).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors approved the final version of the manuscript and the submission to this journal.

Competing interests

The authors declare no competing interests.

Abbreviations

axis Inhibitor 2

apoptotic protease activating factor-1

autophagy-related protein 3

aldehyde dehydrogenase 1

long-chain acyl-CoA synthetase 4

bromodomain-containing protein 4

brahma-related gene-1

bcl-2 assaciated X

bcl-2 antagonist 1

b-cell lymphoma 2-associated transcription factor 1

cellular-myelocytomatosis viral oncogene

stromal cell-derived factor-1

cyclin dependent kinase 19

epithelial mesenchymal transition

enhancer of zeste homolog

fused in sarcoma/translocated in liposarcoma

forkhead box protein M1

growth arrest and DNA damage inducible alpha

glycogen synthase kinase-3β

high mobility group protein A2

high mobility group box 1

heterogeneous nuclear ribonucleoprotein A2B1

lactate dehydrogenase A

non-POU domain-containing octamer-binding protein

octamer-binding transcription factor 4

paraspeckle component 1

phosphoglycerate kinase 1

poly ADP-ribose polymerase-1

tumor protein p53

regulation of nuclear pre-mRNA domain containing 1B

RAD51 recombinase

transcription specificity protein 1

suppressor of cytokine signaling 3

sex determining region Y-box 2

TNF receptor associated factor 6

WD repeat domain 5

zinc finger E-box binding homeobox 2

References

1. Bray F Laversanne M Weiderpass E Soerjomataram I The ever-increasing importance of cancer as a leading cause of premature death worldwide CANCER-AM CANCER SOC 2021 127 16 3029 30 10.1002/cncr.33587 34086348

2. Kaur R Bhardwaj A Gupta S Cancer treatment therapies: traditional to modern approaches to combat cancers MOL BIOL REP 2023 50 11 9663 76 10.1007/s11033-023-08809-3 37828275

3. Ashdown ML, Robinson AP, Yatomi-Clarke SL, Ashdown ML, Allison A, Abbott D, Markovic SN, Coventry BJ. Chemotherapy for Late-Stage Cancer Patients: Meta-Analysis of Complete Response Rates. F1000Res 2015, 4:232. 10.12688/f1000research.6760.1 PMC4706056 26834979

4. Zhao J, Guercio BJ, Sahasrabudhe D. Current Trends in Chemotherapy in the Treatment of Metastatic Prostate Cancer. CANCERS 2023, 15(15). 10.3390/cancers15153969 PMC10417637 37568784

5. Zhang YF Fan Y Zhang P Ruan JY Mu Y Li JK Cervical Cancer recurrence and patient Survival after Radical Hysterectomy followed by either adjuvant chemotherapy or adjuvant Radiotherapy with Optional Concurrent Chemotherapy: a systematic review and Meta-analysis FRONT ONCOL 2022 12 823064 10.3389/fonc.2022.823064 35311123 PMC8931664

6. Colombo N Lorusso D Scollo P Impact of recurrence of Ovarian Cancer on Quality of Life and Outlook for the future INT J GYNECOL CANCER 2017 27 6 1134 40 10.1097/IGC.0000000000001023 28640766 PMC5499966

7. Cabanos HF, Hata AN. Emerging insights into targeted therapy-tolerant Persister cells in Cancer. CANCERS 2021, 13(11). 10.3390/cancers13112666 PMC8198243 34071428

8. Zahreddine H Borden KL Mechanisms and insights into drug resistance in cancer FRONT PHARMACOL 2013 4 28 10.3389/fphar.2013.00028 23504227 PMC3596793

9. Yadav D Rao G Paliwal D Singh A Shadab S Insight into the Basic mechanisms and various modulation strategies involved in Cancer Drug Resistance CURR CANCER DRUG TAR 2023 23 10 778 91 10.2174/1568009623666230508110258 37157204

10. Hu X Wen L Li X Zhu C Relationship between Autophagy and Drug Resistance in Tumors MINI-REV MED CHEM 2023 23 10 1072 8 10.2174/1389557522666220905090732 36065919

11. Zhou X Ao X Jia Z Li Y Kuang S Du C Zhang J Wang J Liu Y Non-coding RNA in cancer drug resistance: underlying mechanisms and clinical applications FRONT ONCOL 2022 12 951864 10.3389/fonc.2022.951864 36059609 PMC9428469

12. Ying Z Wenjing S Jing B Songbin F Kexian D Advances in long non-coding RNA regulating drug resistance of cancer Gene 2023 887 147726 10.1016/j.gene.2023.147726 37625566

13. Bridges MC, Daulagala AC, Kourtidis A. LNCcation: lncRNA localization and function. J CELL BIOL 2021, 220(2). 10.1083/jcb.202009045 PMC7816648 33464299

14. Mattick JS Amaral PP Carninci P Carpenter S Chang HY Chen LL Chen R Dean C Dinger ME Fitzgerald KA Long non-coding RNAs: definitions, functions, challenges and recommendations NAT REV MOL CELL BIO 2023 24 6 430 47 10.1038/s41580-022-00566-8 36596869 PMC10213152

15. Devaux Y Zangrando J Schroen B Creemers EE Pedrazzini T Chang CP Dorn GN Thum T Heymans S Long noncoding RNAs in cardiac development and ageing NAT REV CARDIOL 2015 12 7 415 25 10.1038/nrcardio.2015.55 25855606

16. St LG Wahlestedt C Kapranov P The Landscape of long noncoding RNA classification TRENDS GENET 2015 31 5 239 51 10.1016/j.tig.2015.03.007 25869999 PMC4417002

17. Chen LL Linking long noncoding RNA localization and function TRENDS BIOCHEM SCI 2016 41 9 761 72 10.1016/j.tibs.2016.07.003 27499234

18. Quinn JJ Chang HY Unique features of long non-coding RNA biogenesis and function NAT REV GENET 2016 17 1 47 62 10.1038/nrg.2015.10 26666209

19. Richard J Eichhorn P Deciphering the roles of lncRNAs in breast development and disease Oncotarget 2018 9 28 20179 212 10.18632/oncotarget.24591 29732012 PMC5929455

20. Connerty P Lock RB de Bock CE Long non-coding RNAs: major regulators of cell stress in Cancer FRONT ONCOL 2020 10 285 10.3389/fonc.2020.00285 32266130 PMC7099402

21. Khalili-Tanha G Moghbeli M Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells CELL MOL BIOL LETT 2021 26 1 39 10.1186/s11658-021-00282-9 34425750 PMC8381522

22. Jiang T Zhu J Jiang S Chen Z Xu P Gong R Zhong C Cheng Y Sun X Yi W Targeting lncRNA DDIT4-AS1 sensitizes Triple negative breast Cancer to Chemotherapy via suppressing of Autophagy ADV SCI 2023 10 17 e2207257 10.1002/advs.202207257 PMC10265098 37096846

23. Li Y Gan Y Liu J Li J Zhou Z Tian R Sun R Liu J Xiao Q Li Y Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer SIGNAL TRANSDUCT TAR 2022 7 1 87 10.1038/s41392-022-00902-6 PMC8964798 35351858

24. Li S Li J Chen C Zhang R Wang K Pan-cancer analysis of long non-coding RNA NEAT1 in various cancers GENES DIS 2018 5 1 27 35 10.1016/j.gendis.2017.11.003 30258932 PMC6146416

25. Yang Y Xue J Qin L Zhang J Liu J Yu J LncRNA NEAT1 promotes inflammatory response in Sepsis via the miR-31-5p/POU2F1 Axis INFLAMMATION 2021 44 4 1518 28 10.1007/s10753-021-01436-9 33710444 PMC8285354

26. Liu T Zhang Y Liu W Zhao J LncRNA NEAT1 regulates the development of Parkinson’s Disease by Targeting AXIN1 Via sponging miR-212-3p NEUROCHEM RES 2021 46 2 230 40 10.1007/s11064-020-03157-1 33241432

27. Pan J Hu Y Yuan C Wu Y Zhu X lncRNA NEAT1 promotes the proliferation and metastasis of hepatocellular carcinoma by regulating the FOXP3/PKM2 axis FRONT ONCOL 2022 12 928022 10.3389/fonc.2022.928022 36185217 PMC9521570

28. Ren Y Liu Y He W Zhao W Pan J Gao H Li Y Zhang Y Wang W Expression of NEAT1 can be used as a predictor for Dex resistance in multiple myeloma patients BMC Cancer 2023 23 1 630 10.1186/s12885-023-11084-x 37407915 PMC10320976

29. Bi CL, Liu JF, Zhang MY, Lan S, Yang ZY, Fang JS. LncRNA NEAT1 promotes malignant phenotypes and TMZ resistance in glioblastoma stem cells by regulating let-7 g-5p/MAP3K1 axis. BIOSCIENCE REP 2020, 40(10). 10.1042/BSR20201111 PMC7601351 33057597

30. Chen S Xia X Long noncoding RNA NEAT1 suppresses sorafenib sensitivity of hepatocellular carcinoma cells via regulating miR-335-c-Met J CELL PHYSIOL 2019 234 9 14999 5009 10.1002/jcp.27567 30937906

31. Fox AH Nakagawa S Hirose T Bond CS Paraspeckles: where long noncoding RNA meets phase separation TRENDS BIOCHEM SCI 2018 43 2 124 35 10.1016/j.tibs.2017.12.001 29289458

32. Sasaki YT Ideue T Sano M Mituyama T Hirose T MENepsilon/beta noncoding RNAs are essential for structural integrity of nuclear paraspeckles P NATL ACAD SCI USA 2009 106 8 2525 30 10.1073/pnas.0807899106 PMC2650297 19188602

33. West JA Mito M Kurosaka S Takumi T Tanegashima C Chujo T Yanaka K Kingston RE Hirose T Bond C Structural, super-resolution microscopy analysis of paraspeckle nuclear body organization J CELL BIOL 2016 214 7 817 30 10.1083/jcb.201601071 27646274 PMC5037409

34. Pistoni M Rossi T Donati B Torricelli F Polano M Ciarrocchi A Long noncoding RNA NEAT1 acts as a molecular switch for BRD4 transcriptional activity and mediates repression of BRD4/WDR5 target genes MOL CANCER RES 2021 19 5 799 811 10.1158/1541-7786.MCR-20-0324 33547232

35. Chen Q Cai J Wang Q Wang Y Liu M Yang J Zhou J Kang C Li M Jiang C Long noncoding RNA NEAT1, regulated by the EGFR Pathway, contributes to Glioblastoma Progression through the WNT/beta-Catenin pathway by scaffolding EZH2 CLIN CANCER RES 2018 24 3 684 95 10.1158/1078-0432.CCR-17-0605 29138341

36. Ma P Pan Y Yang F Fang Y Liu W Zhao C Yu T Xie M Jing X Wu X KLF5-Modulated lncRNA NEAT1 contributes to Tumorigenesis by acting as a Scaffold for BRG1 to silence GADD45A in gastric Cancer MOL THER-NUCL ACIDS 2020 22 382 95 10.1016/j.omtn.2020.09.003 PMC7533296 33230443

37. Liang J Liu C Xu D Xie K Li A LncRNA NEAT1 facilitates glioma progression via stabilizing PGK1 J TRANSL MED 2022 20 1 80 10.1186/s12967-022-03273-2 35123484 PMC8818213

38. Jia Y Yan Q Zheng Y Li L Zhang B Chang Z Wang Z Tang H Qin Y Guan XY Long non-coding RNA NEAT1 mediated RPRD1B stability facilitates fatty acid metabolism and lymph node metastasis via c-Jun/c-Fos/SREBP1 axis in gastric cancer J EXP CLIN CANC RES 2022 41 1 287 10.1186/s13046-022-02449-4 PMC9520879 36171622

39. Hu Y, Zai H, Jiang W, Ou Z, Yao Y, Zhu Q. Hepatoblastoma: Derived Exosomal LncRNA NEAT1 Induces BMSCs Differentiation into Tumor-Supporting Myofibroblasts via Modulating the miR-132/MMP9 Axis. J ONCOL 2022, 2022:7630698. 10.1155/2022/7630698 PMC8923764 35300348

40. Yuan J Yang J Wang R Hao H Li J LncRNA NEAT1 regulate diffuse large B-cell lymphoma by targeting miR-495-3p/PD-L1 axis IMMUNOPHARM IMMUNOT 2022 44 3 429 36 10.1080/08923973.2022.2052896 35352617

41. Wei F, Yan Z, Zhang X, Wang Y, Wang M, Zhu Y, Xu K. LncRNA-NEAT1 inhibits the occurrence and development of pancreatic cancer through spongy miR-146b-5p/traf6. BIOTECHNOL GENET ENG 2023:1–19. 10.1080/02648725.2023.2192059 36951525

42. Mao M Zheng X Sheng Y Chai J Ding H Evodiamine inhibits malignant progression of ovarian cancer cells by regulating lncRNA-NEAT1/miR-152-3p/CDK19 axis CHEM BIOL DRUG DES 2023 102 1 101 14 10.1111/cbdd.14228 36892495

43. Xu W Zhou G Wang H Liu Y Chen B Chen W Lin C Wu S Gong A Xu M Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer INT J CANCER 2020 146 10 2901 12 10.1002/ijc.32747 31633800

44. Badowski C He B Garmire LX Blood-derived lncRNAs as biomarkers for cancer diagnosis: the Good, the bad and the Beauty NPJ PRECIS ONCOL 2022 6 1 40 10.1038/s41698-022-00283-7 35729321 PMC9213432

45. Bai J Huang G Role of long non-coding RNA NEAT1 in the prognosis of prostate cancer patients Medicine 2020 99 22 e20204 10.1097/MD.0000000000020204 32481386 PMC12245381

46. Wang Y Zhang D Zhang C Sun Y The Diagnostic and Prognostic Value of serum lncRNA NEAT1 in Colorectal Cancer CANCER MANAG RES 2020 12 10985 92 10.2147/CMAR.S269978 33173332 PMC7646461

47. Li Z Wang D Zhang W Shi H Zhu M Novel PBMC LncRNA signatures as diagnostic biomarkers for colorectal cancer PATHOL RES PRACT 2024 253 154985 10.1016/j.prp.2023.154985 38039742

48. Swellam M El MH Shawki MA Adel M Hefny MM El-Shazly SS Clinical impact of LncRNA XIST and LncRNA NEAT1 for diagnosis of high-risk group breast cancer patients CURR PROB CANCER 2021 45 5 100709 10.1016/j.currproblcancer.2021.100709 33602501

49. Lin NC Hsia SM Wang TH Li PJ Tseng YH Chiu KC Tu HF Shih YH Shieh TM The relation between NEAT1 expression level and survival rate in patients with oral squamous cell carcinoma J DENT SCI 2022 17 1 361 7 10.1016/j.jds.2021.09.018 35028059 PMC8739734

50. Liu Z Wu K Wu J Tian D Chen Y Yang Z Wu A NEAT1 is a potential prognostic biomarker for patients with nasopharyngeal carcinoma J CELL BIOCHEM 2019 120 6 9831 8 10.1002/jcb.28263 30618186

51. Yu H Peng S Chen X Han S Luo J Long non-coding RNA NEAT1 serves as a novel biomarker for treatment response and survival profiles via microRNA-125a in multiple myeloma J CLIN LAB ANAL 2020 34 9 e23399 10.1002/jcla.23399 32608537 PMC7521229

52. Wang P Li QY Sun YN Wang JT Liu M Long noncoding RNA NEAT1: a potential biomarker in the progression of laryngeal squamous cell carcinoma ORL J OTO-RHINO-LARY 2021 83 6 464 70 10.1159/000515228 33831864

53. Li B Gu W Zhu X NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signalling pathway J DRUG TARGET 2019 27 10 1061 7 10.1080/1061186X.2019.1585437 30782035

54. Zang F Rao Y Zhu X Wu Z Jiang H Shikonin suppresses NEAT1 and Akt signaling in treating paclitaxel-resistant non-small cell of lung cancer MOL MED 2020 26 1 28 10.1186/s10020-020-00152-8 32268876 PMC7140387

55. Jiang P Xu H Xu C Chen A Chen L Zhou M Haq IU Wu X Mariyam Z Feng Q NEAT1 contributes to the CSC-like traits of A549/CDDP cells via activating wnt signaling pathway CHEM-BIOL INTERACT 2018 296 154 61 10.1016/j.cbi.2018.10.001 30291867

56. Wei X Tao S Mao H Zhu H Mao L Pei W Shi X Shi Y Zhang S Wu Y Exosomal lncRNA NEAT1 induces paclitaxel resistance in breast cancer cells and promotes cell migration by targeting miR-133b Gene 2023 860 147230 10.1016/j.gene.2023.147230 36717039

57. Li X Wang S Li Z Long X Guo Z Zhang G Zu J Chen Y Wen L The lncRNA NEAT1 facilitates cell growth and invasion via the miR-211/HMGA2 axis in breast cancer INT J BIOL MACROMOL 2017 105 Pt 1 346 53 10.1016/j.ijbiomac.2017.07.053 28720546

58. Zhao W Li W Jin X Niu T Cao Y Zhou P Zheng M Silencing long non-coding RNA NEAT1 enhances the suppression of cell growth, invasion, and apoptosis of bladder cancer cells under cisplatin chemotherapy INT J CLIN EXP PATHO 2019 12 2 549 58 PMC6945077 31933859

59. Zhu M Yang L Wang X NEAT1 Knockdown suppresses the Cisplatin Resistance in Ovarian Cancer by regulating miR-770-5p/PARP1 Axis CANCER MANAG RES 2020 12 7277 89 10.2147/CMAR.S257311 32884343 PMC7434570

60. Yang B Ye X Wang J Xia S Long noncoding RNA nuclear-enriched abundant transcript 1 regulates proliferation and apoptosis of neuroblastoma cells treated by cisplatin by targeting miR-326 through Janus kinase/signal transducer and activator of transcription 3 pathway NeuroReport 2020 31 17 1189 98 10.1097/WNR.0000000000001538 33044324

61. Li X Zhou Y Yang L Ma Y Peng X Yang S Li H Liu J LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma J CELL PHYSIOL 2020 235 4 3402 13 10.1002/jcp.29230 31549407 PMC13482680

62. Mou SJ Yang PF Liu YP Xu N Jiang WW Yue WJ BCLAF1 promotes cell proliferation, invasion and drug-resistance though targeting lncRNA NEAT1 in hepatocellular carcinoma LIFE SCI 2020 242 117177 10.1016/j.lfs.2019.117177 31870774

63. Pouyanrad S Rahgozar S Ghodousi ES Dysregulation of miR-335-3p, targeted by NEAT1 and MALAT1 long non-coding RNAs, is associated with poor prognosis in childhood acute lymphoblastic leukemia Gene 2019 692 35 43 10.1016/j.gene.2019.01.003 30639603

64. Liu F Ai FY Zhang DC Tian L Yang ZY Liu SJ LncRNA NEAT1 knockdown attenuates autophagy to elevate 5-FU sensitivity in colorectal cancer via targeting miR-34a CANCER MED-US 2020 9 3 1079 91 10.1002/cam4.2746 PMC6997058 31802650

65. Zhu Y Hu H Yuan Z Zhang Q Xiong H Hu Z Wu H Huang R Wang G Tang Q LncRNA NEAT1 remodels chromatin to promote the 5-Fu resistance by maintaining colorectal cancer stemness CELL DEATH DIS 2020 11 11 962 10.1038/s41419-020-03164-8 33168814 PMC7653927

66. Hu Y, Yang Q, Wang L, Wang S, Sun F, Xu D, Jiang J. Knockdown of the oncogene lncRNA NEAT1 restores the availability of miR-34c and improves the sensitivity to cisplatin in osteosarcoma. BIOSCIENCE REP 2018, 38(3). 10.1042/BSR20180375 PMC6435545 29654165

67. Adriaens C Standaert L Barra J Latil M Verfaillie A Kalev P Boeckx B Wijnhoven PW Radaelli E Vermi W p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity NAT MED 2016 22 8 861 8 10.1038/nm.4135 27376578

68. Jiang X Guo S Zhang Y Zhao Y Li X Jia Y Xu Y Ma B LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204-5p CELL SIGNAL 2020 65 109422 10.1016/j.cellsig.2019.109422 31672604

69. Huang W Zhang J Dong B Chen H Shao L Li X A novel miR-98 negatively regulates the resistance of Endometrial Cancer cells to Paclitaxel by suppressing ABCC10/MRP-7 FRONT ONCOL 2021 11 809410 10.3389/fonc.2021.809410 34950596 PMC8688247

70. Che F Ye X Wang Y Ma S Wang X Lnc NEAT1/miR-29b-3p/Sp1 form a positive feedback loop and modulate bortezomib resistance in human multiple myeloma cells EUR J PHARMACOL 2021 891 173752 10.1016/j.ejphar.2020.173752 33253679

71. Taiana E Favasuli V Ronchetti D Todoerti K Pelizzoni F Manzoni M Barbieri M Fabris S Silvestris I Gallo CM Long non-coding RNA NEAT1 targeting impairs the DNA repair machinery and triggers anti-tumor activity in multiple myeloma Leukemia 2020 34 1 234 44 10.1038/s41375-019-0542-5 31427718

72. Wu R, Su Z, Zhao L, Pei R, Ding Y, Li D, Zhu S, Xu L, Zhao W, Zhou W. Extracellular Vesicle-Loaded Oncogenic lncRNA NEAT1 from Adipose-Derived Mesenchymal Stem Cells Confers Gemcitabine Resistance in Pancreatic Cancer via miR-491-5p/Snail/SOCS3 Axis. STEM CELLS INT 2023, 2023:6510571. 10.1155/2023/6510571 PMC9902843 36762032

73. Fu X Deng X Xiao W Huang B Yi X Zou Y Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis AM J CANCER RES 2021 11 8 3841 56 34522453 PMC8414385

74. Shao X, Zheng X, Ma D, Liu Y, Liu G. Inhibition of lncRNA-NEAT1 sensitizes 5-Fu resistant cervical cancer cells through de-repressing the microRNA-34a/LDHA axis. BIOSCIENCE REP 2021, 41(7). 10.1042/BSR20200533 PMC8298262 33645623

75. Shoshan-Barmatz V Arif T Shteinfer-Kuzmine A Apoptotic proteins with non-apoptotic activity: expression and function in cancer Apoptosis 2023 28 5–6 730 53 10.1007/s10495-023-01835-3 37014578 PMC10071271

76. Neophytou CM, Trougakos IP, Erin N, Papageorgis P. Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance. CANCERS 2021, 13(17). 10.3390/cancers13174363 PMC8430856 34503172

77. Ngoi N, Choong C, Lee J, Bellot G, Wong A, Goh BC, Pervaiz S. Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer. CANCERS 2020, 12(3). 10.3390/cancers12030574 PMC7139457 32131385

78. Nguyen TT Wei S Nguyen TH Jo Y Zhang Y Park W Gariani K Oh CM Kim HH Ha KT Mitochondria-associated programmed cell death as a therapeutic target for age-related disease EXP MOL MED 2023 55 8 1595 619 10.1038/s12276-023-01046-5 37612409 PMC10474116

79. Otto T Sicinski P Cell cycle proteins as promising targets in cancer therapy NAT REV CANCER 2017 17 2 93 115 10.1038/nrc.2016.138 28127048 PMC5345933

80. Sun Y, Liu Y, Ma X, Hu H. The influence of cell cycle regulation on Chemotherapy. INT J MOL SCI 2021, 22(13). 10.3390/ijms22136923 PMC8267727 34203270

81. Wang JQ Yang Y Cai CY Teng QX Cui Q Lin J Assaraf YG Chen ZS Multidrug resistance proteins (MRPs): structure, function and the overcoming of cancer multidrug resistance DRUG RESIST UPDATE 2021 54 100743 10.1016/j.drup.2021.100743 33513557

82. Pote MS Gacche RN ATP-binding cassette efflux transporters and MDR in cancer DRUG DISCOV TODAY 2023 28 5 103537 10.1016/j.drudis.2023.103537 36801375

83. Feyzizadeh M Barfar A Nouri Z Sarfraz M Zakeri-Milani P Valizadeh H Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery EXPERT OPIN DRUG DIS 2022 17 9 1013 27 10.1080/17460441.2022.2112666 35996765

84. Orlando UD Castillo AF Medrano M Solano AR Maloberti PM Podesta EJ Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression BIOCHEM PHARMACOL 2019 159 52 63 10.1016/j.bcp.2018.11.005 30414939

85. Alhmoud JF, Woolley JF, Al MA, Malki MI. DNA Damage/Repair management in cancers. CANCERS 2020, 12(4). 10.3390/cancers12041050 PMC7226105 32340362

86. Gillman R Lopes FK Wankell M Hebbard L The role of DNA damage and repair in liver cancer BBA-REV CANCER 2021 1875 1 188493 10.1016/j.bbcan.2020.188493 33316376

87. Liu Y Liu G Targeting NEAT1 affects the sensitivity to PARPi in Serous Ovarian Cancer by regulating the homologous recombination repair pathway J CANCER 2024 15 5 1397 413 10.7150/jca.91896 38356722 PMC10861825

88. Ashrafizadeh M, Zarrabi A, Hushmandi K, Kalantari M, Mohammadinejad R, Javaheri T, Sethi G. Association of the Epithelial-Mesenchymal Transition (EMT) with cisplatin resistance. INT J MOL SCI 2020, 21(11). 10.3390/ijms21114002 PMC7312011 32503307

89. Liu F Wang Y Cao Y Wu Z Ma D Cai J Sha J Chen Q Transcription factor B-MYB activates lncRNA CCAT1 and upregulates SOCS3 to promote chemoresistance in colorectal cancer CHEM-BIOL INTERACT 2023 374 110412 10.1016/j.cbi.2023.110412 36812959

90. Xu J Fang X Long L Wang S Qian S Lyu J HMGA2 promotes breast cancer metastasis by modulating Hippo-YAP signaling pathway CANCER BIOL THER 2021 22 1 5 11 10.1080/15384047.2020.1832429 33307962 PMC7834087

91. Yun CW, Jeon J, Go G, Lee JH, Lee SH. The dual role of Autophagy in Cancer Development and a therapeutic strategy for Cancer by Targeting Autophagy. INT J MOL SCI 2020, 22(1). 10.3390/ijms22010179 PMC7795059 33375363

92. Debnath J Gammoh N Ryan KM Autophagy and autophagy-related pathways in cancer NAT REV MOL CELL BIO 2023 24 8 560 75 10.1038/s41580-023-00585-z 36864290 PMC9980873

93. Bahar E, Han SY, Kim JY, Yoon H. Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components. CANCERS 2022, 14(6). 10.3390/cancers14061462 PMC8945922 35326612

94. Zhu X Cong J Lin Z Sun J Yang B Li A Inhibition of HMGB1 overcomes resistance to Radiation and Chemotherapy in Nasopharyngeal Carcinoma ONCOTARGETS THER 2020 13 4189 99 10.2147/OTT.S239243 PMC7236242 32523355

95. Ponomarev A, Gilazieva Z, Solovyeva V, Allegrucci C, Rizvanov A. Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression. CANCERS 2022, 14(4). 10.3390/cancers14040970 PMC8869813 35205716

96. Patil T Rohiwal SS Tiwari AP Stem cells: therapeutic implications in Chemotherapy and Radiotherapy Resistance in Cancer Therapy CURR STEM CELL RES T 2023 18 6 750 65 10.2174/1574888X17666221003125208 36200212

97. Rezayatmand H Razmkhah M Razeghian-Jahromi I Drug resistance in cancer therapy: the Pandora’s Box of cancer stem cells STEM CELL RES THER 2022 13 1 181 10.1186/s13287-022-02856-6 35505363 PMC9066908

98. Alsayed R Sheikhan K Alam MA Buddenkotte J Steinhoff M Uddin S Ahmad A Epigenetic programing of cancer stemness by transcription factors-non-coding RNAs interactions SEMIN CANCER BIOL 2023 92 74 83 10.1016/j.semcancer.2023.04.005 37054905

99. Warburg O Wind F Negelein E THE METABOLISM OF TUMORS IN THE BODY J GEN PHYSIOL 1927 8 6 519 30 10.1085/jgp.8.6.519 19872213 PMC2140820

100. Hu X Guo B Sun T Wang W Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3 OPEN MED-WARSAW 2023 18 1 20230635 10.1515/med-2023-0635 PMC10105522 37069941

101. Zhang Y, Zhang H, Dong J, Zhao P, Hao F, Han H, Bian Y. CAPRIN1 Enhances Chemoresistance and Glycolysis in Laryngeal Squamous Cell Carcinoma via Regulation of ZIC5. J ONCOL 2022, 2022:6160539. 10.1155/2022/6160539 PMC9098336 35571493

102. Sharma D Singh M Rani R Role of LDH in tumor glycolysis: regulation of LDHA by small molecules for cancer therapeutics SEMIN CANCER BIOL 2022 87 184 95 10.1016/j.semcancer.2022.11.007 36371026

103. Lin LC Lee HT Chien PJ Huang YH Chang MY Lee YC Chang WW NAD(P)H:quinone oxidoreductase 1 determines radiosensitivity of triple negative breast cancer cells and is controlled by long non-coding RNA NEAT1 INT J MED SCI 2020 17 14 2214 24 10.7150/ijms.45706 32922184 PMC7484675