Molecular factors associated with lung cancer in people living with HIV.

Introduction

Human Immunodeficiency Virus (HIV), the etiology of the Acquired Human Immunodeficiency Syndrome (AIDS), caused 1.3 million of new infections and 630,000 AIDS-related deaths in 2024, to record 40.8 million (37.0 million–45.6 million) people living with HIV (PLWH). 1

Currently, 77 % of the total infected population have access to the Antiretroviral Therapy (ART). Consequently, the incidence of HIV-related opportunistic infections has been significantly reduced. 1 Nevertheless, high-risk groups among PLWH still exhibit high rates of oropharyngeal and esophageal candidiasis, 2 bacterial pneumonia, 3 herpes zoster 4 and tuberculosis. 5

Moreover, HIV is associated with an increased risk of cancer development, which is a leading cause of HIV-associated death. 6 Cancers directly associated with T-cell immunodeficiency are classified as AIDS-Defining Cancers (ADCs), including Kaposi Sarcoma (KS), Non-Hodgkin Lymphoma (NHL), and cervical cancer. Conversely, non-AIDS-Defining Cancers (NADCs) can occur in both HIV-positive and HIV-negative individuals, although their incidence is higher in people living with HIV. 7

Forty different types of NADCs have been recognized, with approximately half of them being associated with oncogenic viruses such as Epstein-Barr, human papillomavirus and hepatitis B and C viruses. These cancers with infectious etiology such as anal, vulvar, vaginal, Hodgkin lymphoma and liver malignancies exhibit high incidence. NADCs without infectious etiology include mesothelial and soft tissue tumors, multiple myeloma and lung cancer. Notably, people living with HIV show higher progression and mortality rates for these malignancies compared to the HIV-negative population. 8

In this review, we focus on the molecular mechanisms associated with the development of lung cancer as a NADC of clinical relevance. This multifactorial malignancy requires continued research to elucidate its mechanisms of pathogenesis and identify risk factors to implement targeted therapies and preventive strategies.

Literature search strategy

This article is a descriptive review. A comprehensive literature search was conducted in the databases PubMed and Google Scholar. The search focused on key terms related to HIV infection and cancer pathogenesis, including HIV, cancer, oncogenic HIV proteins, lung cancer, non-AIDS-defining cancers, pathogenesis, etiology, and molecular mechanisms. The search was primarily limited to articles published within the last 10-years and written in English. Review articles, epidemiological studies, and treatment-focused studies were excluded during the initial search to prioritize original research addressing molecular and pathogenic mechanisms. Articles were selected based on their relevance to the scope of the review.

HIV pathogenicity

HIV is an enveloped lentivirus that primarily targets CD4+ cells expressing chemokine receptors, particularly CCR5 and CXCR4, which serve as coreceptors during viral entry. The envelope proteins gp120 and gp41 mediate receptor recognition and fusion of the viral envelope with the plasma membrane, allowing entry of the nucleocapsid. 9 Once internalized, the viral RNA is reverse-transcribed into double-stranded DNA while the nucleocapsid migrates to the nucleus. The viral DNA is subsequently imported through nuclear pores and integrated into the host genome. During the late stage of the replication cycle, viral genes are transcribed, the genome is replicated, and newly assembled virions are released from the infected cell. 10

Virions using CCR5 as a coreceptor (R5 viruses) initially target memory CD4+ T -cells, which are enriched in mucosal tissues. This early phase of infection results in a massive CD4+ T -cell destruction by direct viral cytopathic effects, cytotoxic T-lymphocyte-mediated killing, and bystander apoptosis induced by Env-mediated signaling. Acute HIV infection is associated with viral loads ranging from 10 4 to 10 7 RNA copies/mL 11 and leads to the establishment of viral reservoirs, which consist of latently infected cells harboring integrated replication-competent proviruses.

The HIV reservoir is primarily established in resting CD4+ T -cells, which become infected during the transition from an activated to a quiescent state, as well as in myeloid cells residing in different tissues. Accordingly, major viral reservoirs have been identified in the bone marrow, 12 lymph nodes, the gut-associated lymphoid system, spleen, thymus, and central nervous system. 13 , 14

Even though ART is effective in reducing plasma viremia to undetectable levels and has improved the quality of life and expectancy for HIV-infected individuals, it does not eliminate the virus from the latently infected reservoir, which carries inducible proviruses capable of reactivation. 15 Sampling of different CD4+ T -cell subsets from lymph nodes, Gut Associated Lymphoid Tissue (GALT) and peripheral blood mononuclear cells has revealed that these are active anatomical compartments functioning as sanctuaries for HIV persistence. 16 Furthermore, HIV DNA has been detected in specialized macrophage populations such as Kupffer cells, alveolar macrophages and microglia, as well as in mucosal cells of the penile urethra and vagina, contributing to the complexity and heterogeneity of the HIV reservoir. 17

In addition to replication-competent proviruses, some cells harbor defective proviral genomes with internal deletions. Although these defective proviruses are incompetent to produce infectious viruses, they can express viral proteins that contribute to chronic inflammation and T-cell exhaustion. In consequence, there exist increased risk to develop HIV-associated comorbidities such as cardiovascular disease, neurodegeneration and cancer. 18 , 19 , 20

HIV proteins with oncogenic effects

The HIV genome encodes the Gag, Pol and Env genes which express structural, regulatory and accessory proteins ( Fig. 1 ). Among the regulatory proteins, Tat (trans-activator of transcription) and Rev (regulator of RNA splicing) control viral gene transcription, while accessory proteins such as Nef (Negative regulating factor), Vif (Viral infectivity factor), Vpr (Virus protein r ) and Vpu (Virus protein unique) regulate replication, viral budding, immune evasion and pathogenesis. 21 Interestingly, the envelope protein gp120, Nef and Tat have been implicated in HIV-associated oncogenesis. Fig. 1 HIV-1 structural, regulatory and accessory proteins. The Gag gene encodes the structural proteins matrix (p17), capsid (p24) and nucleoprotein (p7), in addition to p6 (not shown) that mediates viral release. The Pol gene encodes the enzymes Reverse Transcriptase (RT), Integrase (IN) and Protease (PR). The Env gene encodes the envelope glycoproteins gp120/gp41. Created with BioRender. Fig. 1 dummy alt text

Tat is a small regulatory protein that increases RNA polymerase II activity during viral genome transcription and downregulates MHC-I expression, contributing to immune evasion and viral persistence. It is secreted at high concentrations in the supernatants of HIV-infected lymphocytes, as well as in serum and cerebrospinal fluid from patients, even under viral control with antiretroviral therapy. 22

Tat has also been linked to modulation of the Tat-Interacting Protein 30 (TIP30), a known tumor suppressor involved in regulating apoptosis, proliferation, metastasis, angiogenesis, DNA repair, and tumor metabolism in various cancers, including Hepatocellular Carcinoma (HCC), colorectal carcinoma, glioma, breast cancer, laryngeal squamous cell carcinoma, esophageal carcinoma, lung cancer, among others. 23

In hepatocellular carcinoma, loss of TIP30 promotes Epithelial-Mesenchymal Transition (EMT). During the EMT the transcription factor Snail is overexpressed; it has been associated with invasive breast cancer cells since it recruits a repressor complex to inhibit E-cadherin transcription. 24 Nuclear translocation of Snail is facilitated by its interaction with importin-β2. Tat interacts with importin-β2 increasing nuclear localization of Snail leading to EMT, enhanced cell motility and poor prognosis by metastasis. 25 , 26

The envelope glycoproteins gp120 and gp41 are membrane-associated proteins, although gp120 can also be released in a soluble form stimulating neighboring cells and altering signaling pathways related to immune response, cell viability and cell cycle regulation. 27 , 28 Particularly, gp120 induces IL-6 production and expansion of myeloid derived suppressor cells with a phenotype CD11b + , CD33 + , HLA-DR -/low , and pSTAT3 hi , which are associated with expansion of regulatory T-cells and immunosuppression. 29 Additionally, gp120 induces apoptosis and disrupt the cell cycle in epithelial, lymphoid and neuronal cells by upregulating cyclin dependent kinase 1 and proapoptotic effectors such as Bax, Fas/FasL, caspase 3 and caspase 8. 30 , 31

Soluble gp120 has also profibrotic activity in human hepatic stellate cells through interaction with CXCR4 and subsequent ERK1/2 phosphorylation, triggering collagen I expression. This process possibly accelerate liver fibrosis in HIV positive individuals, especially those coinfected with hepatitis C virus. 32

In epithelial cells, both gp120 and Tat upregulate markers of EMT, such as N-cadherin and vimentin, along with downregulation of E-cadherin and cytokeratin. 33 Immunohistochemical analysis of cervical cancer tissues from HIV-positive women coinfected with Human Papillomavirus (HPV) show diminished expression of E-cadherin and cytokeratin, whereas vimentin is increased with respect to tissues from HIV-negative patients, suggesting that gp120 and Tat induce EMT and facilitate the progression of HPV-associated cervical lesions. 33

On the other hand, the regulatory protein Nef is expressed early after infection and manipulates host cell processes to increase viral replication and persistence. Nef modulates T-cell activation by internalization and lysosomal degradation of CD4 and CD28. Promotes indirectly viral infectivity of CD4 + T -cells through production of CCL2 and CCL4 in macrophages, which results in chemotaxis and activation of T-lymphocytes, which become permissive to HIV ( Fig. 2 ). 34 Nef also contributes to immune evasion avoiding antigen presentation by interfering of the trafficking of HLA-I, reducing recognition of infected cells by cytotoxic lymphocytes. 35 Its role in modulating stability of viral and cellular proteins that participate in virus replication via the ubiquitin proteasome system has been described by proteomic analysis. 36 Actually, Nef interacts with the ubiquitin E3 ligase E6AP to induce p53 ubiquitination and proteasomal degradation. 37 P53 is a transcriptional regulator in response to DNA damage induced by ultraviolet light, gamma radiation and carcinogens. Loss of p53 function impairs cell cycle control and apoptosis, allowing genetically damaged cells to survive and accumulate oncogenic mutations. 38 Fig. 2 HIV entry is mediated by the interaction of the viral envelope proteins gp120/gp41 with the host cell molecules CD4 (primary receptor) and CCR5 or CXCR4 (main coreceptors). After the Reverse Transcriptase (RT) enzyme synthesize the viral DNA and it is imported to the nucleus, the integrase inserts the viral DNA into the host-cell chromosomes. The transcription, replication and translation of the viral genome are mediated by hijacked cellular components, which allows for the synthesis of all necessary components to assemble a new viral progeny. HIV replication is optimized by processes such as immune evasion and cell survival. The viral protein Tat not only increases viral transcription but also reduces the expression of MHC-I in epithelial and lymphoid cells. Both Tat and gp120 induce expression of vimentin while E-cadherin is downregulated, an event associated with the EMT. In addition, soluble gp120 induces the synthesis of IL-6, which indirectly promotes the expansion of Treg lymphocytes, upregulates CDK1 (to alter the cell cycle), and induces the expression of proapoptotic molecules. Nef modulates the stability of both viral and cellular proteins by ubiquitination (e.g., inducing p53 degradation via the proteasome) and increases the expression of the enzyme ATIC, which upregulates the proto-oncogene Myc in lung cancer. Created with BioRender. Fig. 2 dummy alt text

In addition, Nef increases the expression of the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), which participates in the purine biosynthetic pathway. 36 ATIC is upregulated in myeloma and HCC. Also, this enzyme is overexpressed in advanced stages of lung adenocarcinoma and promotes cell growth and migration through upregulation of the proto-oncogen Myc. 39

Lung cancer, as all types of cancers, is multifactorial and particularly, in people living with HIV, immunosuppression, chronic inflammation, smoking and the oncogenic HIV proteins are interconnected triggering factors. In the following sections we summarize epidemiology, evidence of HIV persistence in lungs and molecular mechanisms associated with lung cancer in PLWH.

Lung cancer in PLWH

Lung cancer is the most common NADC and the leading cause of cancer-related deaths in PLWH. 40 , 41 Histologically, it is classified in two main types: Non-Small Cell Lung Cancer (NSCLC) and small cell lung cancer. NSCLC is a heterogeneous group of epithelial malignancies that account for 86 %–94 % of lung cancers; the main subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. 42 Adenocarcinoma is the most frequent subtype (30 %–50 %).

The incidence of lung cancer in patients with HIV represents a notable disparity compared to the general population. Epidemiological studies indicate that PLWH have 1.5–3-fold increased risk of developing lung cancer, compared with the HIV-negative population. 42 , 43

A study using data from the multicenter CoRIS Spanish cohort (2004‒2021) reported 176 deaths associated with non-AIDS-defining tumors, of which, 36.4 % were related to lung cancer (mortality rate of 0.57, 95 % CI 0.45, 0.73). Lung cancer was associated with a 2-fold increase in mortality in PLWH. The risk of mortality was also higher in association with factors such as coinfection with hepatitis B and C viruses, heterosexual HIV transmission, use of injected drugs, active smoking, and CD4 counts < 500 µL. 44

Another study that analyzed data from the HIV/AIDS Cancer Match Study (USA) from 2001 to 2016 estimated a significant decrease in the incidence of lung cancer among individuals with HIV: incidence rates were 124.4 per 100,000 person-years during 2001 to 2003, compared to 58.3 per 100,000 person-years in the period from 2013 to 2016. However, the incidence rates remained 48 % higher in HIV + individuals than in the general population. 42 Such decrease could be associated with increased access to ART; however, immune recovery is incomplete in a proportion of patients and may represent a persistent risk factor for lung cancer. In particular, a low CD4/CD8 ratio, a low nadir CD4+ T -cell count and residual or intermittent viremia despite ART have been associated with higher incidence of this malignancy in PLWH. Moreover, aging and pulmonary infections related to chronic inflammation (e.g., tuberculosis) may also contribute to cancer risk. Of relevance, lung cancer diagnosis in PLWH has been associated with decreased median survival compared with general population (12.4 vs. 22.8-months). 41 , 42 , 43

HIV persistence in lung tissue

In addition to the gut-associated lymphoid tissue, other long-term HIV reservoirs have been identified. 45 Particularly, HIV provirus has been quantified in Bronchioalveolar Lavages (BAL) and Peripheral Blood Leucocytes (PBLs) from patients living with HIV that developed respiratory symptoms. Results revealed higher levels of proviral DNA in BAL derived cells (2971 HIV DNA copies/10 6 cells), compared to PBLs (391 HIV DNA copies/10 6 lung cells). Interestingly, viral genome can be detected even in patients receiving nucleoside reverse-transcriptase inhibitors, although with reduced levels (up to 6-fold decrease). 46

HIV DNA has also been quantified in BAL from patients without respiratory symptoms, under ART and with a minimum of 3-years of viral suppression. In this case, BAL derived cells showed higher HIV DNA copies than PBMCs (13-fold); particularly, effector memory CD4 + T -cells were the principal HIV reservoir. Interestingly, the pulmonary CD4 + T -cell population showed an enrichment of CD57 + cells that are associated with immuno-senescence, whereas T-regulatory Foxp3 + cells were also increased. Thirty percent of the patients showed HIV RNA in BAL derived cells, indicating active viral genome transcription. 47

Notably, Nef + cells (CD4 + , CD8 + and alveolar macrophages) have been evidenced in BAL from patients with undetectable levels of p24 and genomic RNA. Therefore, persistent expression of HIV regulatory proteins in lung tissue and other anatomical sites contribute to tissue damage, immunosuppression and cancer development. 48

Mechanisms associated with lung cancer in HIV

Virus derived components and extracellular vesicles

Studies in human respiratory tract derived cell lines indicate that Nef induces cell proliferation and migration, as well as apoptosis resistance when it is transfected in A549 cells and non-cancerous BEAS-2B cells. Also, Nef increases expression of angiogenesis and tissue remodeling factors such as Nuclear Factor of Activated T-cells-1 (NFAT-1), Matrix Metalloproteinase-9 (MMP-9) and Vascular Endothelial Growth Factor (VEGF-A) whereas it reduces p53 protein levels ( Table 1 ). 49 Processing of micro-RNA (miRNAs) is also altered in BEAS-2B cells transfected with Nef, since this viral protein significantly reduces the level of expression of the enzymes DICER and Ago2. Consequently, miRNAs associated with lung cancer are downregulated, indicating this viral protein impairs miRNA biogenesis, contributing to tumor development and cancer progression. 49 Table 1 Function of proteins differentially altered in lung cancer tissues. Table 1 dummy alt text Molecule Role in cancer Up or down regulation in lung cancer Reference NFAT-1 Controls cell cycle, migration, invasion and apoptosis. Induce angiogenesis and matrix metalloproteinases expression. Up 57 MMP-9 Metalloproteinase-9, promotes tumor invasion and metastasis by tissue remodeling and angiogenesis. Up 49 VEGF-A Vascular Endothelial Growth Factor-A participates in angiogenesis, cell proliferation, migration and survival. Associated with immunosuppression in the tumor microenvironment. Up 49 EMAP-II Endothelial monocyte-activating polypeptide-II. Antiangiogenic cytokine that inhibits tumor growth and metastasis by inducing apoptosis. Up 48 FOS Proto-oncogene. Regulates cell proliferation, differentiation, stress response and apoptosis. Its overexpression is associated with metastasis. Up 75 DEFB103 Beta-defensin. Regulates inflammatory response by modulating cytokines and chemokines. Involved in cell proliferation. Up 52 c-Myc Oncogene that regulates cell proliferation, metabolism and evasion of the host immune response, promoting cancer progression. Up 39 SIX1 Sine Oculis Homeobox. Transcription factor involved in organ development during embryogenesis and in disorders such as cancer. Reactivates developmental programs. Up 76 PROM1 Prominin-1. Membrane glycoprotein. Marker of cancer stem cells; it enhances tumorigenesis, metastasis, treatment resistance, and activation of pathways such as Wnt/β-catenin, PI3K-Akt, as well as VEGF-A/IL-8 production. Up 54 TFAP2A Oncogenic factor. Promotes tumor proliferation and angiogenesis. Also inhibits apoptosis. Member of the AP-2 transcription factors family. Up 54 TOX3 Thymocyte selection-associated HMG BOX. Promotes proliferation, migration, invasion, resistance to apoptosis, and maintenance of the stem-like phenotype. Up 77 SOX9 Transcription factor that regulates embryonic development, tissue differentiation, and maintenance of cancer stem cells. It promotes proliferation, invasion, resistance to apoptosis, and EMT. Up 78 ADH1B Catalyzes the oxidation of ethanol to acetaldehyde. It acts as an acetaldehyde detoxifier and prevents persistent oxidative stress. Down 54 INMT Indolethylamine N-methyltransferase. Tumor suppressor by limiting cell proliferation, migration and invasion. Down 54 SYNPO2 Synaptopodin-2 directs cytoskeletal organization, limits proliferation, migration, invasion and EMT. Participates in autophagy Down 53 P16 INK4a Inhibits the cell cycle and induces cellular senescence by blocking CDK4/6, preventing RB phosphorylation. Induces cell cycle arrests avoiding G1/S transition. Down 79 P53 Tumor suppressor. Regulates the cell cycle, induces apoptosis, and maintains genomic stability. Down 38 DICER Endoribonuclease. Promotes post-transcriptional gene silencing by processing pre-miRNA to mature single-stranded forms. Down 49 Ago2 Argonaute 2, participates in biogenesis and function of miRNAs and siRNAs. Down 80 PTEN Tumor suppressor. Controls chromatin condensation, centromere stability, accurate chromosome segregation and DNA replication. Down 56

Interestingly, Nef has been detected in Bronchioalveolar Lavages (BAL) of HIV patients under ART, both into cells and Extracellular Vesicles (EVs). Nef + -EVs isolated from HEK 293T cells transfected with Nef induced expression and release of TNF-α, IL-6, MCP-1, CXCL10 and RANTES in primary human alveolar macrophages, contributing to chronic inflammation and increasing the risk for lung cancer. Also, Nef induced upregulation of the cytokine Endothelial Monocyte-Activating Polypeptide-II (EMAP-II), which is involved in oxidative stress and apoptosis, as well as in the pathogenesis of emphysema. 48 Worth to mention that emphysema is a predisposing factor for lung cancer, 50 as long-term inflammation involves pulmonary tissue damage and remodeling. 51

On the other hand, it has been identified EVs with Gag and gp160 as cargo proteins, as well as the HIV Transactivation Response (TAR) RNA element that regulates viral transcription. EVs isolated from HIV-infected T-cells in vitro induced proliferation and migration of human head and neck squamous carcinoma cell lines. Such effect can be reproduced with EVs derived from plasma of HIV-infected individuals under ART, with respect to EVs from healthy individuals. Notably, the HIV-TAR RNA cargo was the effector element involved in expression of the proto-oncogenes FOS, DEFB103 and c-Myc through phosphorylation of ERK1/2 in an EGFR/TLR3-dependent manner, to induce expression of the proto-oncogenes. 52

Lung cancer tissues derived from HIV+ patients have been studied to determine their transcriptional profile. A study with lung biopsies from lung adenocarcinomas, squamous cell carcinomas and small cell lung cancer indicated the most importantly upregulated genes were SIX1, PROM1, TFAP2A, TOX3 and SOX9, whereas ADH1B, INMT and SYNPO2 were significantly downregulated, in comparison with paired adjacent non-tumor tissues. Of such altered genes, SYNPO2 is a potential tumor suppressor in diverse types of cancers, whereas SIX1 has been associated with tumor development and progression. Also, SIX1 is a potential biomarker of clinical prognosis of patients with non-small cell lung cancer. 53 , 54

Effect of HIV integration into the host DNA and epigenetics

The HIV genome preferentially integrates into transcriptionally active genes. Proviral integration in genes related to cell growth has been observed in approximately 12.7 % of PBMCs, increasing to 16.0 % in proliferating cells. Gene ontology analysis indicated that unique HIV integrations were enriched in genes from cell proliferation pathways such as MAPK1, BACH2, C2CD3, CREBBP, FBX11, DNMT1, among others. 55

A study in a patient with diagnosis of small cell lung carcinoma showed 174 unique HIV integration sites in lung tumor tissue, of which, 30 % were identified in clonally expanded cells. Viral DNA was principally integrated in the Phosphatase and Tensin Homolog (PTEN) gene that encodes an enzyme with phosphatase activity. Phosphatidylinositol-3,4,5-trisphosphate (PIP3) is a second messenger that triggers the PI3K/AKT pathway to promote cell survival, proliferation and differentiation. Active PTEN dephosphorylates the PIP3 to 4,5-bisphosphate acting as a tumor suppressor. 56 Histopathological analysis showed that tissue regions expressing p24 showed loss of expression of PTEN protein, 57 suggesting that PTEN downregulation contributes to lung cancer development and progression.

Notably, PTEN and other genes involved in cell cycle and DNA repair have been found hypermethylated in non-small cell lung cancer, particularly at promoter regions in CpG islands. 58

Another gene silenced in early stages of non-small cell lung cancers by hypermethylation is the tumor suppressor p16 INK4a , 59 which regulates cell cycle progression by inhibiting the S phase. 60 Interestingly, acute HIV infection of Hut 78 cells increases expression of the DNA methylase DNMT1 along with hypermethylation of the p16 INK4a promoter which is associated with significantly reduced gene transcription. 61

Thus, epigenetics plays a significant role in lung cancer development, and patterns of methylation of specific genes in the Wnt signaling pathway can be used as prognostic biomarkers. 62

Altered immune response and oxidative stress

During HIV infection, T-cells are persistently stimulated and activated by viral antigens. This condition eventually triggers T-cell exhaustion associated with impaired cytokine production, upregulation of inhibitory receptors such as PD-1, CTLA-4 and TIM-3, as well as reduced proliferative potential. Functional T-cell damage leads to poor elimination of pathogens and cancer cells. 63

On the other hand, a chronic state of oxidative stress has been described in PLWH. 64 Reactive Oxygen and Nitrogen Species (ROS and RNS) are produced during lung inflammation, mainly by activated alveolar macrophages, neutrophils and epithelial cells. 65 Oxidative stress is produced by an imbalance between oxidants and antioxidant effectors. The antioxidant activity is mediated by enzymes such as superoxide dismutase, catalase, glutathione peroxidase and thioredoxin. 66 ROS alter the activity of transcription factors such as STAT-1, MAPKs and NF-kB to trigger inflammatory signals. Persistent exposure to ROS and RNS promotes macrophage senescence. 67

Interestingly, primary alveolar macrophages from PLWH without respiratory symptoms release significantly increased levels of the superoxide anion, whereas their bronchioalveolar lavages display reduced levels of the antioxidant glutathione, in comparison to HIV negative individuals. 68

A transgenic rat model expressing gp120 and Tat, but unable to assemble viral particles showed reduced levels of glutathione in lungs compared to wild type rats. In addition, pulmonary epithelium displayed increased paracellular permeability associated with reduced levels of the adhesion molecules zonula occludens-1 and occludin in the alveolar epithelium; such effect was related to the expression of the viral proteins. 69 Also, mice expressing Tat in the lungs showed cellular infiltration and oxidative stress associated with higher levels of nitrotyrosine, manganese superoxide dismutase, and NF-kB (p65), supporting the role of Tat to induce the oxidative environment. 70

Therefore, the oxidative stress mediated by HIV-proteins impairs the alveolar epithelial barrier by decreasing antioxidant effectors and altering expression of intercellular adhesion proteins. However, free radicals also produce genomic instability and trigger signaling pathways related to oncogene expression (e.g. Jun and Fos). 71 Of interest, overexpression of Jun-D has been directly associated with lung cancer. 72

Finally, smoking is a major risk factor for lung cancer in the general population and increases the risk up to five-fold in HIV + patients. 73 Potent carcinogens and immunosuppressive molecules derived from the combustion of tobacco such as isoprene, benzene, benzo[a]pyrene, carbon monoxide, hydrogen cyanide, nitric oxide, ROS, among others, alter lung function and contribute to systemic inflammation enhancing susceptibility to infections and development of malignancies. 74

Concluding

The molecular interplay between HIV infection and lung cancer development involves a complex network of viral proteins, host signaling pathways, and epigenetic regulators ( Fig. 3 and Table 1 ). Proteins such as Tat, Nef, and gp120 modulate oncogenic processes, including cell cycle dysregulation, apoptosis inhibition, epithelial-mesenchymal transition, angiogenesis, and immune evasion allowing virus persistence. Persistent viral reservoirs within lung tissue sustain local inflammatory and immunosuppressive microenvironments that stimulate cell transformation. Concurrently, HIV integration into host DNA and increased gene methylation contribute to the silencing of tumor suppressor genes. Also, extracellular vesicles carrying viral components maintain pro-tumorigenic signaling. Fig. 3 Interacting network of altered genes in lung tissues and cells derived from lung malignancies from PLWH. The list of genes from Table 1 was analyzed in STRING, Version 12.0. Two clusters were identified that, as expected, are related with cancer development and the TNF signaling pathway involving proinflammatory genes. As mentioned in the main text, *PTEN, *SIX1 and p16 INK4a (also known as *CDKN2A) are potential biomarkers of lung cancer prognosis.TP53 is synonym of p53. Fig. 3 dummy alt text

Future research should prioritize the construction of comprehensive interaction networks to enable the identification of molecular causal factors driving lung cancer progression in PLWH. Such integrative approaches may help to identify early prognostic biomarkers. At present, molecules such as PTEN, SIX1 and p16 INK4a have been described as prognostic biomarkers in human lung cancer, while Ago2 and DICER1 might be considered as molecules with potential prognostic application in this type of malignancy. From a therapeutic perspective, focusing on these biomarkers may provide a rationale for future studies to explore new strategies to combine antiretroviral drugs with targeted inhibitors of key effectors in oncogenic signaling pathways. In addition, public-health campaigns could be developed to emphasize the harmful effects of smoking, particularly among PLWH, to reduce predisposing factors for lung cancer.

Authors' contributions

BRID, FNJ and RTE designed, collected data and wrote the manuscript; RHDL contributed to writing and prepared illustrations. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI) , Mexico, project CBF2023-2024-2356 .

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of interest

The authors declare no conflicts of interest.

References

1 Geneva: Joint United, Nations Programme on HIV/AIDS; Joint United Nations Programme on HIV/AIDS (UNAIDS), 2025. AIDS, crisis and the power to transform: UNAIDS Global AIDS update 2025. 2025.

2 Patil S. Majumdar B. Sarode S.C. Sarode G.S. Awan K.H. Oropharyngeal candidosis in HIV-infected patients ‒ an update Front Microbiol 9 2018 980 29867882 10.3389/fmicb.2018.00980 PMC5962761

3 Schleenvoigt B.T. Ankert J. Barten-Neiner G. Voit F. Suttorp N. Boesecke C. Pathogen spectrum of community acquired pneumonia in people living with HIV (PLWH) in the German CAPNETZ-cohort Infection 52 2024 129 137 37423969 10.1007/s15010-023-02070-3 PMC10811115

4 Trentacapilli B. Raccagni A.R. Diotallevi S. Nozza S. Lolatto R. D’Amelio A.C. Implementation of recombinant anti-herpes zoster vaccination in people living with HIV: a single-center experience Front Virol 5 2025 1537821

5 Sossen B. Kubjane M. Meintjes G. Tuberculosis and HIV coinfection: progress and challenges towards reducing incidence and mortality Int J Infect Dis 155 2025 107876 10.1016/j.ijid.2025.107876 40064284

6 Anastasia A. Mazzucco W. Pipitò L. Fruscione S. Gaudiano R. Trizzino M. Malignancies in people living with HIV: a 25-years observational study from a tertiary hospital in Italy J Infect Public Health 18 2025 102661 10.1016/j.jiph.2025.102661 39813856

7 Engels E.A. Non-0002030-defining malignancies in HIV-infected persons: etiologic puzzles, epidemiologic perils, prevention opportunities AIDS 23 2009 875 885 19349851 10.1097/QAD.0b013e328329216a PMC2677638

8 Yuan T. Hu Y. Zhou X. Yang L. Wang H. Li L. Incidence and mortality of non-AIDS-defining cancers among people living with HIV: a systematic review and meta-analysis eClinicalMedicine 52 2022 101613 10.1016/j.eclinm.2022.101613 PMC9386399 35990580

9 Chen B. Molecular mechanism of HIV-1 entry Trends Microbiol 27 2019 878 891 31262533 10.1016/j.tim.2019.06.002 PMC6744290

10 Freed E.O. HIV-1 assembly, release and maturation Nat Rev Microbiol 13 2015 484 496 26119571 10.1038/nrmicro3490 PMC6936268

11 Picker L.J. Watkins D.I. HIV pathogenesis: the first cut is the deepest Nat Immunol 6 2005 430 432 15843796 10.1038/ni0505-430

12 Kuo H.H. Lichterfeld M. Recent progress in understanding HIV reservoirs Curr Opin HIV AIDS 13 2018 137 142 29232209 10.1097/COH.0000000000000441 PMC5806203

13 Churchill M.J. Deeks S.G. Margolis D.M. Siliciano R.F. Swanstrom R. HIV reservoirs: what, where and how to target them Nat Rev Microbiol 14 2016 55 60 26616417 10.1038/nrmicro.2015.5

14 Henderson L.J. Reoma L.B. Kovacs J.A. Nath A. Advances toward curing HIV-1 infection in tissue reservoirs Pierson TC, editor J Virol 94 2020 e00375 - 10.1128/JVI.00375-19 PMC7000960 31694954

15 Fromentin R. Bakeman W. Lawani M.B. Khoury G. Hartogensis W. DaFonseca S. CD4+ T cells expressing PD-1, TIGIT and LAG-3 contribute to HIV persistence during ART Douek DC, editor PLoS Pathog 12 2016 e1005761 10.1371/journal.ppat.1005761 PMC4944956 27415008

16 De Scheerder M.A. Vrancken B. Dellicour S. Schlub T. Lee E. Shao W. HIV rebound is predominantly fueled by genetically identical viral expansions from diverse reservoirs Cell Host Microbe 26 2019 347 358 e7 31471273 10.1016/j.chom.2019.08.003 PMC11021134

17 Chen J. Zhou T. Zhang Y. Luo S. Chen H. Chen D. The reservoir of latent HIV Front Cell Infect Microbiol 12 2022 945956 10.3389/fcimb.2022.945956 PMC9368196 35967854

18 Kuniholm J. Coote C. Henderson A.J. Defective HIV-1 genomes and their potential impact on HIV pathogenesis Retrovirology 19 2022 13 35764966 10.1186/s12977-022-00601-8 PMC9238239

19 Imamichi H. Smith M. Adelsberger J.W. Izumi T. Scrimieri F. Sherman B.T. Defective HIV-1 proviruses produce viral proteins Proc Natl Acad Sci USA 117 2020 3704 3710 32029589 10.1073/pnas.1917876117 PMC7035625

20 Akiyama H. Jalloh S. Park S. Lei M. Mostoslavsky G. Gummuluru S. Expression of HIV-1 intron-containing RNA in microglia induces inflammatory responses Simon V, editor J Virol 95 2021 e01386-20 10.1128/JVI.01386-20 PMC8092841 33298546

21 Guenzel C.A. Hérate C. Benichou S. HIV-1 Vpr-a still "enigmatic multitasker" Front Microbiol 5 2014 127 24744753 10.3389/fmicb.2014.00127 PMC3978352

22 Clark E. Nava B. Caputi M. Tat is a multifunctional viral protein that modulates cellular gene expression and functions Oncotarget 8 2017 27569 27581 28187438 10.18632/oncotarget.15174 PMC5432358

23 Xu T. Jin Z. Yuan Y. Zheng H. Li C. Hou W. Tat-interacting protein 30 (TIP30) expression serves as a new biomarker for tumor prognosis: a systematic review and Meta-analysis Ahmad A, editor PLoS One 11 2016 e0168408 10.1371/journal.pone.0168408 PMC5201241 28036326

24 Wu Y. Zhou B.P. Snail: more than EMT Cell Adhes Migr 4 2010 199 203 10.4161/cam.4.2.10943 PMC2900613 20168078

25 Zhu M. Yin F. Fan X. Jing W. Chen R. Liu L. Decreased TIP30 promotes snail-mediated epithelial–mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma Oncogene 34 2015 1420 1431 24681951 10.1038/onc.2014.73

26 Liu Y. Chen C. Yen C. Tung C. Chen C. Chen Y.A. Human immunodeficiency virus tat- TIP 30 interaction promotes metastasis by enhancing the nuclear translocation of snail in lung cancer cell lines Cancer Sci 109 2018 3105 3114 30099830 10.1111/cas.13768 PMC6172071

27 Cheung R. Ravyn V. Wang L. Ptasznik A. Collman R.G. Signaling mechanism of HIV-1 gp120 and virion-induced IL-1β release in primary human macrophages J Immunol 180 2008 6675 6684 18453587 10.4049/jimmunol.180.10.6675 PMC2375537

28 Elalouf A. Maoz H. Rosenfeld A.Y. Comprehensive insights into the molecular basis of HIV glycoproteins Appl Sci 14 2024 8271

29 Garg A. Spector S.A. HIV type 1 gp120–induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity J Infect Dis 209 2014 441 451 23999600 10.1093/infdis/jit469 PMC3883171

30 Morou A.K. Porichis F. Krambovitis E. Sourvinos G. Spandidos D.A. Zafiropoulos A. The HIV-1 gp120/V3 modifies the response of uninfected CD4 T cells to antigen presentation: mapping of the specific transcriptional signature J Transl Med 9 2011 160 21943198 10.1186/1479-5876-9-160 PMC3203262

31 Saro A. Gao Z. Kambey P.A. Li M. Huang J. HIV-1 gp120 protein activates cyclin-dependent kinase 1, a possible link to central nervous system cell death Viruses 14 2022 2793 36560797 10.3390/v14122793 PMC9786227

32 Hong F. Saiman Y. Si C. Mosoian A. Bansal M.B. X4 human immunodeficiency virus type 1 gp120 promotes human hepatic stellate cell activation and collagen I expression through interactions with CXCR4 Zheng JC, editor PLoS One 7 2012 e33659 10.1371/journal.pone.0033659 PMC3313947 22479424

33 Wang P. Yang B. Huang H. Liang P. Long B. Chen L. HIV gp120/Tat protein-induced epithelial–mesenchymal transition promotes the progression of cervical lesions AIDS Res Ther 20 2023 82 37981694 10.1186/s12981-023-00577-1 PMC10657494

34 Swingler S. Mann A. Jacqué J.M. Brichacek B. Sasseville V.G. Williams K. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages Nat Med 5 1999 997 1003 10470075 10.1038/12433 PMC9513713

35 Wonderlich E.R. Leonard J.A. Collins K.L. HIV immune evasion: disruption of antigen presentation by the HIV Nef protein Adv Virus Res 80 2011 103 127 21762823 10.1016/B978-0-12-385987-7.00005-1 PMC3782996

36 Ghaly M. Proulx J. Borgmann K. Park I.W. Novel role of HIV-1 Nef in regulating the ubiquitination of cellular proteins Front Cell Infect Microbiol 13 2023 1106591 10.3389/fcimb.2023.1106591 PMC10031067 36968110

37 Ali A. Farooqui S.R. Rai J. Singh J. Kumar V. Mishra R. HIV-1 Nef promotes ubiquitination and proteasomal degradation of p53 tumor suppressor protein by using E6AP Biochem Biophys Res Commun 529 2020 1038 1044 32819562 10.1016/j.bbrc.2020.05.188

38 Chen X. Zhang T. Su W. Dou Z. Zhao D. Jin X. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation Cell Death Dis 13 2022 974 36400749 10.1038/s41419-022-05408-1 PMC9674619

39 Niu N. Zeng J. Ke X. Zheng W. Fu C. Lv S. ATIC facilitates cell growth and migration by upregulating Myc expression in lung adenocarcinoma Oncol Lett 23 2022 131 35251351 10.3892/ol.2022.13251 PMC8895470

40 Okuma Y. Hishima T. Kashima J. Homma S. High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer Cancer Immunol Immunother 67 2018 495 505 29243049 10.1007/s00262-017-2103-y PMC11028207

41 Hysell K. Yusuf R. Barakat L. Virata M. Gan G. Deng Y. Decreased overall survival in HIV-associated non-small-cell lung cancer Clin Lung Cancer 22 2021 e498 e505 33468393 10.1016/j.cllc.2020.11.006 PMC8169710

42 Haas C.B. Engels E.A. Horner M.J. Freedman N.D. Luo Q. Gershman S. Trends and risk of lung cancer among people living with HIV in the USA: a population-based registry linkage study Lancet HIV 9 2022 e700 e708 36179753 10.1016/S2352-3018(22)00219-3 PMC9641618

43 Hernández-Ramírez R.U. Shiels M.S. Dubrow R. Engels E.A. Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study Lancet HIV 4 2017 e495 e504 28803888 10.1016/S2352-3018(17)30125-X PMC5669995

44 Suárez-García I. Gutierrez F. Pérez-Molina J.A. Moreno S. Aldamiz T. Valencia Ortega E. Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up J Cancer Res Clin Oncol 149 2023 18161 18171 38008809 10.1007/s00432-023-05500-9 PMC10725373

45 Banga R. Perreau M. The multifaceted nature of HIV tissue reservoirs Curr Opin HIV AIDS 19 2024 116 123 38547340 10.1097/COH.0000000000000851 PMC10990014

46 Clarke J.R. Gates A.J. Coker R.J. Douglass J.A. Williamson J.D. Mitchell D.M. HIV-1 proviral DNA copy number in peripheral blood leucocytes and bronchoalveolar lavage cells of AIDS patients Clin Exp Immunol 96 2008 182 186 10.1111/j.1365-2249.1994.tb06539.x PMC1534888 8187325

47 Costiniuk C.T. Salahuddin S. Farnos O. Olivenstein R. Pagliuzza A. Orlova M. HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy AIDS 32 2018 2279 2289 30102653 10.1097/QAD.0000000000001962 PMC6200382

48 Chelvanambi S. Bogatcheva N.V. Bednorz M. Agarwal S. Maier B. Alves N.J. HIV-nef protein persists in the lungs of aviremic patients with HIV and induces endothelial cell death Am J Respir Cell Mol Biol 60 2019 357 366 30321057 10.1165/rcmb.2018-0089OC PMC6397978

49 Santerre M. Chatila W. Wang Y. Mukerjee R. Sawaya B.E. HIV-1 Nef promotes cell proliferation and microRNA dysregulation in lung cells Cell Cycle 18 2019 130 142 30563405 10.1080/15384101.2018.1557487 PMC6343720

50 Li Y. Swensen S.J. Karabekmez L.G. Marks R.S. Stoddard S.M. Jiang R. Effect of emphysema on lung cancer risk in smokers: a computed tomography–based assessment Cancer Prev Res 4 2011 43 50 10.1158/1940-6207.CAPR-10-0151 PMC3018159 21119049

51 Mouronte-Roibás C. Leiro-Fernández V. Fernández-Villar A. Botana-Rial M. Ramos-Hernández C. Ruano-Ravina A. COPD, emphysema and the onset of lung cancer. A systematic review Cancer Lett 382 2016 240 244 27666776 10.1016/j.canlet.2016.09.002

52 Chen L. Feng Z. Yue H. Bazdar D. Mbonye U. Zender C. Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA Nat Commun 9 2018 4585 30389917 10.1038/s41467-018-07006-2 PMC6214989

53 Zheng Z. Song Y. Synaptopodin-2: a potential tumor suppressor Cancer Cell Int 23 2023 158 37544991 10.1186/s12935-023-03013-6 PMC10405370

54 Zheng J. Wang L. Cheng Z. Pei Z. Zhang Z. Li Z. Molecular changes of lung malignancy in HIV Infect Sci Rep 8 2018 13128 10.1038/s41598-018-31572-6 PMC6120915 30177858

55 Wagner T.A. McLaughlin S. Garg K. Cheung C.Y.K. Larsen B.B. Styrchak S. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection Science 345 2014 570 573 25011556 10.1126/science.1256304 PMC4230336

56 Bergez-Hernández F. Irigoyen-Arredondo M. Martínez-Camberos A. A systematic review of mechanisms of PTEN gene down-regulation mediated by miRNA in prostate cancer Heliyon 10 2024 e34950 10.1016/j.heliyon.2024.e34950 PMC11320309 39144981

57 Smith D.M. Rowland E.F. Gianella S. Patel S.P. Solso S. Dullano C. HIV integration into the PTEN gene and its tumor microenvironment implications for lung cancer Curr Oncol 32 2025 389 40710199 10.3390/curroncol32070389 PMC12294024

58 lei Wang J zhen Lu F Shen X.Y. Wu Y. ting Zhao L SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation Biochem Biophys Res Commun 455 2014 229 233 25449277 10.1016/j.bbrc.2014.10.153

59 Belinsky S.A. Nikula K.J. Palmisano W.A. Michels R. Saccomanno G. Gabrielson E. Aberrant methylation of p16 INK4a is an early event in lung cancer and a potential biomarker for early diagnosis Proc Natl Acad Sci USA 95 1998 11891 11896 9751761 10.1073/pnas.95.20.11891 PMC21736

60 Romagosa C. Simonetti S. López-Vicente L. Mazo A. Lleonart M.E. Castellvi J. p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors Oncogene 30 2011 2087 2097 21297668 10.1038/onc.2010.614

61 Fang J.Y. Mikovits J.A. Bagni R. Petrow-Sadowski C.L. Ruscetti F.W. Infection of lymphoid cells by integration-defective human immunodeficiency virus type 1 increases de novo methylation J Virol 75 2001 9753 9761 11559808 10.1128/JVI.75.20.9753-9761.2001 PMC114547

62 Paschidis K. Zougros A. Chatziandreou I. Tsikalakis S. Korkolopoulou P. Kavantzas N. Methylation analysis of APC, AXIN2, DACT1, RASSF1A and MGMT gene promoters in non-small cell lung cancer Pathol Res Pr 234 2022 153899 10.1016/j.prp.2022.153899 35489124

63 Fenwick C. Joo V. Jacquier P. Noto A. Banga R. Perreau M. T-cell exhaustion in HIV infection Immunol Rev 292 2019 149 163 31883174 10.1111/imr.12823 PMC7003858

64 Masiá M. Padilla S. Fernández M. Rodríguez C. Moreno A. Oteo J.A. Oxidative stress predicts all-cause mortality in HIV-infected patients Pacheco AG, editor PLoS One 11 2016 e0153456 10.1371/journal.pone.0153456 PMC4844170 27111769

65 Rahman I. Adcock I.M. Oxidative stress and redox regulation of lung inflammation in COPD Eur Respir J 28 2006 219 242 16816350 10.1183/09031936.06.00053805

66 Forman H.J. Torres M. Redox signaling in macrophages Mol Asp Med 22 2001 189 216 10.1016/s0098-2997(01)00010-3 11679166

67 Danish M. Diwan B. Kumar A. Khan M.A. Awasthi A. Sharma L. Comparative evaluation of cellular senescence in naturally aged and stress-induced murine macrophages for identifying optimum senescent macrophage study systems Mol Biol Rep 52 2025 123 39812869 10.1007/s11033-025-10232-9

68 Buhl R. Imbalance between oxidants and antioxidants in the lungs of HIV-seropositive individuals Chem Biol Interact 91 1994 147 158 8194131 10.1016/0009-2797(94)90035-3

69 Lassiter C. Fan X. Joshi P.C. Jacob B.A. Sutliff R.L. Jones D.P. HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction AIDS Res Ther 6 2009 1 19193217 10.1186/1742-6405-6-1 PMC2644707

70 Cota-Gomez A. Flores A.C. Ling X.F. Varella-Garcia M. Flores S.C. HIV-1 tat increases oxidant burden in the lungs of transgenic mice Free Radic Biol Med 51 2011 1697 1707 21855628 10.1016/j.freeradbiomed.2011.07.023 PMC3188365

71 Lee I.T. Yang C.M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases Biochem Pharmacol 84 2012 581 590 22587816 10.1016/j.bcp.2012.05.005

72 Ruiz E.J. Lan L. Diefenbacher M.E. Riising E.M. Da Costa C. Chakraborty A. JunD, not c-jun, is the AP-1 transcription factor required for Ras-induced lung cancer JCI Insight 6 2021 e124985 10.1172/jci.insight.124985 PMC8410048 34236045

73 Ranjit S. Kumar S. Recent advances in cancer outcomes in HIV-positive smokers F1000Res 7 2018 718 10.12688/f1000research.12068.1 PMC5998002 29946425

74 Rossouw T.M. Anderson R. Feldman C. Impact of HIV infection and smoking on lung immunity and related disorders Eur Respir J 46 2015 1781 1795 26250491 10.1183/13993003.00353-2015

75 Peng L. Sun E. Zhang J. Cai L. Zheng J. Zeng Y. The effect of c-Fos on the prognosis, proliferation, and invasion of oral squamous cell carcinoma Oral Dis 30 2024 4266 4277 38326698 10.1111/odi.14892

76 Ford H.L. Landesman-Bollag E. Dacwag C.S. Stukenberg P.T. Pardee A.B. Seldin D.C. Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein J Biol Chem 275 2000 22245 22254 10801845 10.1074/jbc.M002446200

77 Liang C. Huang S. Zhao Y. Chen S. Li Y. TOX as a potential target for immunotherapy in lymphocytic malignancies Biomark Res 9 2021 20 33743809 10.1186/s40364-021-00275-y PMC7981945

78 Aldaz P. Otaegi-Ugartemendia M. Saenz-Antoñanzas A. Garcia-Puga M. Moreno-Valladares M. Flores J.M. SOX9 promotes tumor progression through the axis BMI1-p21CIP Sci Rep 10 2020 357 31941916 10.1038/s41598-019-57047-w PMC6962164

79 Zhang X. Wang J. Tang K. Yang Y. Liu X. Yuan S. The cell cycle regulator p16 promotes tumor infiltrated CD8+ T cell exhaustion and apoptosis Cell Death Dis 15 2024 339 38750022 10.1038/s41419-024-06721-7 PMC11096187

80 Liu X. Meng X. Peng X. Yao Q. Zhu F. Ding Z. Impaired AGO2/miR-185-3p/NRP1 axis promotes colorectal cancer metastasis Cell Death Dis 12 2021 390 33846300 10.1038/s41419-021-03672-1 PMC8042018

Acknowledgments

The authors thank Carlos Santiago-Olivares for comments to this manuscript.