MiR-98-5p Contributes To Cisplatin-resistance In Epithelial Ovarian Cancer By Targeting Dicer1,A Key Gene For MiRNA Processing

Background and Purpose: Epithelial ovarian cancer(EOC)is one of the most common and the leading cause of deaths from gynecological malignancies.Platinum resistance is a major challenge in the clinical treatment of ovarian cancer.Therefore,it is crucial to investigate the mechanisms of platinum resistance in EOC patients and develop new strategies for EOC treatment.A number of studies have reported functions of miRNA in regulating chemoresistance in ovarian cancer.Our previous study found that high miR-98-5p expression was associated with platinum resistance.This study aimed to investigate the function and the potential mechanism of miR-98-5p in EOC.Method: The expression of miR-98-5p in EOC cell lines and clinical samples was examined by qRT-PCR and ISH.The effect of miR-98-5p on the sensitivity of cisplatin in EOC cells was tested by CCK-8 and clonogenic assay.The target of miR-98-5p was predicted by database and confirmed by western blot,qRT-PCR and luciferase assays.By miRNA sequencing,we screened out a subset of miRNAs downstream of the miR-98-5p/Dicer1 axis.The functional miRNA was validated by in vitro and in vivo experiments.Results: 1.miR-98-5p was significantly up-regulated in human EOC tissues and cell lines.2.miR-98-5p could directly target the 3’-UTR of Dicer1 and promote cisplatin resistance in EOC cells.3.miR-152 was confirmed as a key downstream miRNA that miR-98-5p / Dcier1 functions by miRNA sequencing.4.miR-152 could enhance the sensitivity of EOC cells to cisplatin by targeting RAD51,a key protein in HR pathway.5.The miR-98-5p/Dicer1/miR-152 axis plays an important role in cisplatin resistance of EOC cells by affecting HR pathway activity.Conclusion: This study explored the miR-98-5p expression in EOC tissues and its function in resistance to cisplatin in EOC cells.Our data firstly suggested the potential role of the miR-98-5p/Dicer1/miR-152 axis in cisplatin resistance.These results provide miR-98-5p and miR-152 as novel predictive and prognostic factors for EOC and the design of novel miRNA-based therapeutic strategies against EOC.