miR-519d-3p/HIF-2α axis increases the chemosensitivity of human cervical cancer cells to cisplatin via inactivation of PI3K/AKT signaling

Cisplatin (DDP)-based chemotherapy is a standard treatment for cervical cancer, although chemotherapy resistance remains a major concern. Hypoxia-inducible factor-2 alpha (HIF-2 alpha) plays an important role in chemotherapy resistance. MicroRNAs (miRs) can inhibit gene expression by binding to the 3 '-untranslated region of the target gene. The authors' previous study showed that miR-519d-3p plays an important role in the regulation of HIF-2 alpha expression under hypoxic conditions in cervical cancer. However, the function and regulatory mechanisms of the miR-519d-3p/HIF-2 alpha axis in DDP-resistance in cervical cancer are not fully understood. Therefore, the aim of the present study was to investigate whether the miR-519d-3p/HIF-2 alpha axis increased DDP resistance by regulating the PI3K/AKT signaling pathway. It was found that the expression of miR-519d-3p was lower in DDP-resistant cervical cancer cells (CaSki/DDP and HeLa/DDP) compared with CaSki and HeLa cells under hypoxic conditions. Additionally, miR-519d-3p overexpression decreased the IC50 value in CaSki/DDP and HeLa/DDP cells, and inhibited HIF-2 alpha protein expression and the PI3K/AKT signaling pathway under hypoxic conditions. Furthermore, it was demonstrated that HIF-2 alpha overexpression reduced the effect of miR-519d-3p overexpression on HeLa/DDP and CaSki/DDP cells. Moreover, the present results suggested that HIF-2 alpha overexpression increased the IC50 value in CaSki/DDP and HeLa/DDP cells. It was also found that HIF-2 alpha overexpression reduced the effect of miR-519d-3p overexpression on the PI3K/AKT signaling pathway. Therefore, the present results indicated that the miR-519d-3p/HIF-2 alpha axis increased DDP resistance of cervical cancer cells by suppressing the PI3K/AKT signaling pathway under hypoxic conditions.