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

چکیده اصلی

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.

ترجمه فارسی چکیده

پروتئین حاوی تکرار WD و SOCS باکس ۱ (WSB1) پیشرفت و متاستاز تومور را تشویق می‌کند، اما نقش آن در پاسخ به گرما درمانی همراه با شیمی‌درمانی و رادیوتراپی در سرطان گردن رحم نامشخص است. این مطالعه نقش WSB1 و محور c-Myc/Wnt/β-catenin در اثرات ضد توموری این درمان ترکیبی را بررسی کرد. بیان WSB1 در خطوط سلولی سرطان گردن رحم بررسی شد و نقش‌های عملکردی آن با آزمون‌های مختلف سلولی ارزیابی شد. تحلیل‌های ژنتیکی نشان دادند که c-Myc مستقیماً WSB1 را فعال می‌کند و WSB1 برای فعال‌سازی سیگنال‌دهی Wnt/β-catenin مورد نیاز است. درمان ترکیبی گرما درمانی و شیمی‌درمانی، ویژگی‌های توموری را در vitro و رشد تومور را در vivo مهار کرد و بیان WSB1 و اجزای مسیر Wnt/β-catenin را کاهش داد.

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