Olaparib increases chemosensitivity by upregulating miR-125a-3p in ovarian cancer cells.

Objective: Ovarian cancer is associated with the highest mortality rate among all malignant gynecological tumors. PolyADP-ribose polymerase (PARP) inhibitor maintenance therapy is the standard treatment strategy for this type of cancer, and olaparib is a widely used oral PARP inhibitor for tumors with BRCA mutations. The present study aimed to investigate the effects of olaparib in non-BRCA-mutated ovarian cancer and the potential mechanisms involved.

Methods: The antitumor effect of cisplatin alone or in combination with olaparib was analyzed in an ovarian cancer subcutaneous transplantation tumor model in nude mice. Furthermore, the differences in microRNA (miRNA) expression levels were analyzed using miRNA arrays. In addition, the effects of miR-125a-3p on the proliferation of non-BRCA-mutated (A2780 and OVCAR-3) ovarian cancer cells were detected using A Cell Counting Kit-8 and changes in the cell cycle were detected using flow cytometry. Furthermore, SPiDER-βGal was used to detect expression changes in cellular senescence, and the expression of DNA damage repair proteins was detected using western blot analysis.

Results: The results revealed that cisplatin plus olaparib significantly reduced tumor volume in mice subjected to subcutaneous tumor transplantation, and the expression of miR-125a-3p significantly increased with this treatment combination. The overexpression of miR-125a-3p could inhibit cell migration, invasion and induces cell cycle arrest.

Conclusion: On the whole, the present study demonstrates that the increased expression of miR-125a-3p induces DNA damage and senescence in ovarian cancer cells, which enhances the therapeutic sensitivity.