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Elevated VAMP8 Expression Promotes Cervical Cancer Progression by Enhancing Autophagy via HIF-1 Pathway

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306495 | GEO | 2025/08/30

REPOSITORIES: GEO

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Project description:Although high-risk human papillomavirus (HPV) infection plays a major role in the development of cervical cancer, additive oncogenic events are involved as well. One key event involves increased activity of telomerase resulting from a deregulated expression of its catalytic subunit hTERT. Our previous microcell-mediated chromosome transfer studies revealed that introduction of human chromosome 6 in the HPV16 immortalized keratinocyte cell line FK16A and in the HPV16 containing cervical cancer cell line SiHa induced growth arrest, resulting from a repression of hTERT mRNA expression and telomerase activity. Here, this model was used to analyze expression profiles associated with hTERT deregulation in HPV transformed cells. Microarray expression analysis of 12 FK16A/chromosome 6 hybrids, four of which were negative for endogenous hTERT and 8 of which were positive for endogenous hTERT, resulted in the identification of 164 differentially expressed genes. Differential expression of a selection of 5 genes was verified by real-time RT-PCR. Of these 164 genes, 32 were also differentially expressed in other HPV transformed cells with deregulated hTERT. For 2 of these genes, encoding AQP3 and MGP, altered expression in hTERT positive cervical carcinomas was confirmed by real-time RT-PCR and immunohistochemistry, respectively. In summary we identified 32 candidate biomarkers for deregulated hTERT mRNA expression which may enable the identification of cervical premalignant lesions that are at highest risk to progress to invasive cancer. Keywords: microarray expression analysis, hTERT, cervical cancer 12 previously established cell hybrids, all carrying the same genetic background were subjected to microarray expression analysis. These hybrids were generated by the introduction of chromosome 6 in the HPV16 immortalized cell line FK16A, which resulted in a suppression of hTERT expression and telomerase activity. 8 hybrids were endogenous hTERT positive and 8 hybrids were hTERT negative. Additionally primary keratinocytes (hTERT negative), parental cell line FK16A and cervical cancer cell line SiHa (both hTERT positive) were hybridized.

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Elevated VAMP8 Expression Promotes Cervical Cancer Progression by Enhancing Autophagy via HIF-1 Pathway

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