HIF-3α-Induced miR-630 Expression Promotes Cancer Hallmarks in Cervical Cancer Cells by Forming a Positive Feedback Loop

Background: Hypoxia has crucial functions in cervical cancer development and metastasis by inducing the level of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Methods: We used RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing experiments (ChIP-seq) to investigate the targets of HIF-3α or miR-630. ChIP-qPCR and RT-qPCR were used to validate the sequencing results of ChIP-seq and RNA-seq. Cellular, molecular and radiation experiments were used to explore the functions of miR-630. Results: Here, we show that hypoxia-induced overexpression HIF-3α increased the expression of dozens of miRNAs, including miR-630. Further experiment showed the activation of miR-630 was induced by hypoxia treatment. We showed that hypoxia induces expression of HIF-3α to activate miR-630 expression by directly binding to its promoter. Meanwhile, miR-630 positively regulates HIF-1α expression, but represses HIF-1α. Stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Stable inhibition of miR-630 showed opposite features. Conclusion: Taken together, our findings implicate a novel hypoxia-induced HIF3a-miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells, and suggest HIF3a and miR630 might be applied as a potential biomarker and therapeutic target for cervical cancer.