Hyperthermia sensitizes cervical cancer to chemoradiotherapy by downregulating c-Myc/WSB1/β-catenin expression.

Background

WD repeat and SOCS box containing protein 1 (WSB1) promotes tumor progression and metastasis; however, its role in the response to hyperthermia combined with chemoradiotherapy in cervical cancer remains unclear. Therefore, this study investigated the involvement of WSB1 and the c-Myc/Wnt/β-catenin axis in the antitumor effects of this combined treatment.

Methods

WSB1 expression was examined in multiple cervical cancer cell lines, and its functional roles were evaluated using the cell counting kit-8, colony formation, wound healing, Transwell migration/invasion, and apoptosis assays. The c-Myc-mediated transcriptional regulation of WSB1 was analyzed using chromatin immunoprecipitation and dual-luciferase reporter assays. Wnt/β-catenin signaling activity and DNA damage were assessed via western blotting and immunofluorescence. Antitumor efficacy was further evaluated in a cervical cancer xenograft model treated with hyperthermia, chemoradiotherapy, or both.

Results

WSB1 was highly expressed in both HeLa and SiHa cells and promoted proliferation, migration, and invasion, while inhibiting apoptosis. c-Myc directly transcriptionally activated WSB1, and WSB1 was required for c-Myc-driven activation of Wnt/β-catenin signaling, thereby forming a positive feedback loop. Combined hyperthermia and chemoradiotherapy markedly suppressed malignant phenotypes in vitro and tumor growth in vivo, increased DNA damage, and downregulated c-Myc, WSB1, and Wnt/β-catenin pathway components, with minimal systemic toxicity.

Conclusions

WSB1 acts as an oncogenic driver in cervical cancer by sustaining c-Myc/Wnt/β-catenin signaling across different histological subtypes. Axis disruption via combined hyperthermia and chemoradiotherapy effectively inhibits tumor progression. This presents WSB1 and its signaling network as potential therapeutic targets for a broad range of patients with cervical cancer.