TSPAN8-mediated Epithelial-mesenchymal Transition Drives Acquired Radioresistance in Cervical Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Acquired radioresistance is a significant challenge in cervical cancer treatment, often linked to epithelial-mesenchymal transition (EMT).
• Identifying novel regulators of EMT-mediated radioresistance is crucial for overcoming treatment failure.

Purpose of the Study:

• To investigate the role of TSPAN8 in regulating EMT-driven radioresistance in cervical cancer.
• To explore TSPAN8 as a potential biomarker and therapeutic target for improving radiotherapy outcomes.

Main Methods:

• Established radioresistant cervical cancer cell lines (HeLa-R25, SiHa-R25) via fractionated irradiation.
• Assessed radioresistance, apoptosis, EMT markers, and stemness using clonogenic survival, flow cytometry, immunoblotting, and immunofluorescence.
• Utilized microarray, protein-protein interaction analysis, co-immunoprecipitation, TSPAN8 manipulation (overexpression/knockdown), xenograft models, immunohistochemistry, and TCGA data analysis.

Main Results:

• Fractionated irradiation induced EMT and radioresistance, characterized by E-cadherin loss and N-cadherin/Vimentin upregulation.
• TSPAN8 was significantly upregulated, directly interacted with E-cadherin, and its overexpression enhanced EMT and radioresistance.
• TSPAN8 knockdown reversed EMT, restored radiosensitivity, suppressed tumor growth in vivo, and correlated with poor patient survival and recurrence.

Conclusions:

• TSPAN8 is a novel regulator of EMT-mediated radioresistance in cervical cancer.
• Elevated TSPAN8 is associated with recurrence, metastasis, and adverse patient outcomes.
• TSPAN8 represents a promising therapeutic target to enhance radiosensitivity and personalize radiotherapy.