Elevated VAMP8 Expression Promotes Cervical Cancer Progression by Enhancing Autophagy via HIF-1 Pathway
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ABSTRACT:
PROVIDER: PRJNA1310981 | ENA |
REPOSITORIES: ENA
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Project description:Background: Cervical cancer, prevalent in low- and middle-income countries, is primarily caused by high-risk HPV16. Vesicle-Associated Membrane Protein 8 (VAMP8), involved in vesicle trafficking and autophagy, may influence HPV16-related cervical cancer progression. Methods: VAMP8 expression was evaluated in cervical tissue specimens from patients with HPV16-positive lesions (including low- and high-grade squamous intraepithelial lesions and cancer) and HPV-negative normal controls using proteomics, qPCR, and immunohistochemistry. A Cox proportional hazards model for prognosis was developed using immunohistochemical data from a cohort of cervical cancer patients. The clinical significance of VAMP8 was further assessed using RNA-seq and clinical data from The Cancer Genome Atlas-Cervical Cancer (TCGA-CESC) cohort. The effects of VAMP8 on autophagy and tumor progression were examined in HPV16 E6/E7-immortalized cervical epithelial cells (Ect1/E6E7) and cervical cancer cell lines (SiHa, HeLa, C-33A) in vitro, and in a SiHa xenograft model in vivo. Transcriptomic analysis of Ect1/E6E7 and SiHa cells identified VAMP8-regulated pathways. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays in SiHa cells were used to confirm the regulation of the HIF-1 pathway. Results: VAMP8 was upregulated in HPV16-positive samples, particularly in low-grade squamous intraepithelial lesions (LSIL). Elevated VAMP8 correlated with poor survival outcomes and advanced tumor stages. VAMP8 enhanced autophagy and reduced proliferation and invasiveness in HPV16-positive cervical cells but increased in established cancer cell lines. In vivo, VAMP8 overexpression promoted tumor growth and autophagy. The HIF-1 pathway emerged as a key regulatory axis of VAMP8, enhancing hypoxic responses and angiogenesis. Conclusion: Elevated VAMP8 in HPV16-associated cervical cancer promotes tumor progression by enhancing autophagy via the HIF-1 pathway, suggesting its potential as a diagnostic and prognostic biomarker.
2025-08-30 | GSE306495 | GEO
Project description:Methylation modifications play pertinent roles in regulating gene expression and various biological processes. The silencing of the demethylated modifier TET1 can affect the expressions of key oncogenes or tumor suppressor genes, thus contributing to tumor formation. Nonetheless, how TET1 affects the progression of cervical cancer is yet to be elucidated. In this study, we found that the expression of TET1 was significantly downregulated in cervical cancer tissues. Functionally, TET1 knockdown in cervical cancer cells can promote cell proliferation, migration, invasion, cervical xenograft tumor formation and EMT. On the contrary, its overexpression can reverse the aforementioned processes. Moreover, the autophagy level of cervical cancer cells can be enhanced after TET1 knockdown. Mechanistically, methylated DNA immunoprecipitation (MeDIP)-sequencing and MeDIP quantitative real-time PCR revealed that TET1 mediates the methylation of autophagy promoter regions. These findings suggest that TET1 affects the malignant biological behavior of cervical cancer cells by altering the methylation levels of autophagy genes NKRF and HIST1H2AK, but the specific mechanism needs to be investigated further.
2024-03-13 | GSE236396 | GEO
Project description:Methylation modifications play pertinent roles in regulating gene expression and various biological processes. The silencing of the demethylated modifier TET1 can affect the expressions of key oncogenes or tumor suppressor genes, thus contributing to tumor formation. Nonetheless, how TET1 affects the progression of cervical cancer is yet to be elucidated. In this study, we found that the expression of TET1 was significantly downregulated in cervical cancer tissues. Functionally, TET1 knockdown in cervical cancer cells can promote cell proliferation, migration, invasion, cervical xenograft tumor formation and EMT. On the contrary, its overexpression can reverse the aforementioned processes. Moreover, the autophagy level of cervical cancer cells can be enhanced after TET1 knockdown. Mechanistically, methylated DNA immunoprecipitation (MeDIP)-sequencing and MeDIP quantitative real-time PCR revealed that TET1 mediates the methylation of autophagy promoter regions. These findings suggest that TET1 affects the malignant biological behavior of cervical cancer cells by altering the methylation levels of autophagy genes NKRF and HIST1H2AK, but the specific mechanism needs to be investigated further.
2024-03-13 | GSE236315 | GEO
Project description:Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. For the molecular mechanism, we used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.
2023-09-24 | GSE158531 | GEO
Project description:Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. For the molecular mechanism, we used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.
2023-09-24 | GSE158530 | GEO
Project description:Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. For the molecular mechanism, we used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.
2023-09-24 | GSE158529 | GEO
Project description:For hematopoietic stem and progenitor cells (HSPCs), hypoxia is a specific microenvironment known as the hypoxic niche. The role of hypoxia in maintaining quiescence, self-renewal and proliferation of HSPCs has been more elaborated. What remains unclear is the regulation of hypoxia on HSPC differentiation, especially on the differentiation of HSPCs into erythrocytes. In this study, we show that hypoxia evidently accelerates erythroid differentiation, and in this process effectively enhances autophagy which rapidly supplies cellular components through degradation of organelles or proteins to meet the needs of cell stress or development. In order to ascertain whether autophagy mediates the erythroid differentiation promoted by hypoxia, we analyze the perturbation of erythroid differentiation after pharmacological and genetic interference with autophagy, and address that autophagy is required for hypoxia-accelerated erythroid differentiation. Transcriptomics reveals HIF-1 and mTORC1 pathways may function as the upstream of autophagy to regulate erythroid differentiation under hypoxia. We further determine that mTORC1 signaling is suppressed by hypoxia to relieve its inhibition of autophagy. In addition, we also discover a new regulatory pattern that with the process of erythroid differentiation, mTORC1 activity gradually decreases and autophagy activity increases concomitantly. Moreover, we provide evidence that HIF-1 target gene REDD1, which inhibits mTORC1 activity, is dramatically upregulated under hypoxia. Silencing REDD1 expression activates mTORC1 signaling and impairs the enhanced autophagy and the accelerated erythroid differentiation under hypoxia. Together, our study reveals that hypoxia is conductive to accelerating erythroid differentiation, in which autophagy induced by the HIF-1/REDD1/mTORC1 pathway plays a pivotal role.
2022-04-04 | GSE199778 | GEO
Project description:We utilised our in vitro model of cervical neoplastic progression, W12, to investigate the effect of HPV16 viral oncogene depletion on well-defined integrant- and episome- associated series. To target HPV16 viral oncogenes we used our previously published E7-targeting siRNA sequence that caused substantial depletion of both E7 and E6 in CaSki cells. We found all E7-siRNA treated W12 series underwent widespread autophagy and senescence, with up-regulation of an innate immune response.
2013-08-12 | E-MTAB-1331 | biostudies-arrayexpress
Project description:Proinflammatory activation of hepatic macrophages plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the placement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that HIF-2a mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2a stimulated mTOR and ERK-dependent inhibitory TFEB phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2a-dependent TFEB regulation only occurred in KCs, but not in RHMs. Instead, in RHMs, HIF-2a promoted mtROS production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Taken together, our results suggest that macrophage subtype-specific effects of HIF-2a collectively contributes to the proinflammatory activation of liver macrophages, leading to the development of NASH.
2025-05-06 | PXD040457 | Pride
Project description:Hypoxia-inducible factor-1 (HIF-1) is a master regulator of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits PHD3 to PKM2 to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with hnRNPF to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly rescues their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
2021-01-19 | GSE159490 | GEO