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Multi-proteomics investigation of the early response to X-rays and carbon ion irradiation of HeLa cells

ABSTRACT: Despite the considerable decline of cervical cancer incidence in developed countries, the disease remains a public health problem in low-income and middle-income countries due to the low popularity of human papillomavirus vaccination and cervical cancer screening. Mainly treated with radiotherapy, the number of recurrences linked to radioresistance increases in women suffering from this disease and constitutes a major obstacle. Here, we perform a multi-proteomics investigation of the early response to X-rays and carbon ion irradiation of HeLa cells in order to highlight the mechanisms of cell radioresistance.

ORGANISM(S): Homo Sapiens

SUBMITTER: François Chevalier

PROVIDER: PXD060187 | iProX | Fri Jan 24 00:00:00 GMT 2025

REPOSITORIES: iProX

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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.

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Multi-proteomics investigation of the early response to X-rays and carbon ion irradiation of HeLa cells

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