HNF1α Contributes to Radio-Resistance in Cervical Cancer Via Regulating the CircHNF1α/miR-204-3p/RAD51D Regulatory Axis

Abstract Background: Radiotherapy as an important primary treatment has effectively improved the survival of patients with cervical cancer (CC). However, some patients do not show optimal benefits of radiotherapy due to radio-resistance. Therefore, identification of biomarkers of radio-resistance and unraveling the underlying mechanisms of radio-resistance is a key imperative for these patients.Methods: The expression levels of circHNF1α, miRNAs, and mRNA in tissues and cell lines were detect by qRT-PCR analysis. The levels of proteins were analyzed by western blot. Cell proliferation ability was measured by colony formation assay. RNA pull-down and uciferase reporter assay analysis were performed to identify the sponging microRNAs of circHNF1α. The target gene of miR-204-3p was determined by luciferase reporter assay. Chromatin immunoprecipitation (ChIP) analysis and luciferase reporter assay were performed to identify the transcription factor of circHNF1α. Results: We found significant upregulation of HNF1α expression in radio-resistant cervical cancer tissues and cell lines. Depletion of HNF1α reduced whereas overexpression of HNF1α promoted the resistance of CC cells to irradiation in vitro and in vivo. HNF1α positively regulated RAD51D at the protein level but not at the mRNA level, thus attenuating radio-resistance of CC cells. Mechanistically, upregulation of HNF1α enhanced circHNF1α transcription and promoted circHNF1α biogenesis, which in turn sponged miR-204-3p and thus relieved their repression of the RAD51D expression. The HFN1α/circHNF1α/miR-204-3p/RAD51D regulatory axis was found to play a critical role in conferring radio-resistance of CC cells.Conclusions: Dysregulation of the HFN1α/circHNF1α/miR-204-3p/RAD51D axis may promote the radio-resistance of CC cells. Blocking this pathway may provide therapeutic benefits against CC radio-resistance.