Hypoxia promotes progression of cervical cancer by modulating the ATXN3-enhanced P53 stability or STAT5 phosphorylation

This study examines hypoxia's role in regulating ATXN3 (ATXN3) across cervical cancer subtypes and its impact on tumor progression. We analyzed ATXN3 expression in clinical samples and cell lines (C33A, HeLa, SiHa), assessing proliferation/migration/invasion after ATXN3 modulation. The study investigated whether ATXN3 is regulated by hypoxia through hypoxia-inducible factor 1α (HIF-1α). Downstream mechanisms were explored using clinical samples and cell lines, comparing P53 and signal transducer and activator of transcription 5 (STAT5)/p-STAT5 levels between cancer tissues and adjacent non-cancerous tissues, and assessing changes following ATXN3 manipulation. ATXN3 was downregulated in human papillomavirus(HPV18⁺) cervical adenocarcinoma but upregulated in HPV16⁺ cervical squamous cell carcinoma. ATXN3 suppressed malignant behaviors in C33A and HeLa but promoted them in SiHa. HIF-1α expression was elevated in cancer tissues versus non-cancerous tissues, with hypoxic conditions differentially regulating ATXN3 via HIF-1α across cell lines. Cervical cancer tissues showed lower P53 and higher p-STAT5 (in HPV16+ squamous cell carcinoma). ATXN3 overexpression stabilized P53 in C33A/HeLa and increased p-STAT5 in SiHa, with inverse effects upon silencing. The findings suggest that hypoxia promotes the progression of subtypes of cervical cancer by regulating ATXN3-enhanced P53/p-STAT5 levels, which may provide a novel therapeutic strategy for clinical applications.