miR-211 facilitates platinum chemosensitivity by blocking the DNA damage response (DDR) in ovarian cancer

Abstract

The DNA damage response (DDR) is one of the most important mechanisms of platinum resistance in ovarian cancer. Some miRNAs have been identified to be involved in the regulatory network of DDR, thus the abnormal expression of miRNAs might affect platinum chemosensitivity in ovarian cancer. In this study, by assessing miRNAs simultaneously targeting a set of DDR genes that exhibited response to platinum, we found that miR-211 inhibited most of those genes, and proposed that miR-211 might affect the sensitivity of ovarian cancer cells to platinum by targeting multiple DDR genes and thereby determine the prognosis of ovarian cancer. To verify the hypothesis, we analyzed the association between miR-211 level and clinical prognosis, assessed the effect of miR-211 on DDR and platinum chemosensitivity, and explored the possible molecular mechanism. We revealed that miR-211 enhanced platinum chemosensitivity and was positively correlated with favorable outcomes in ovarian cancer patients. Many DDR genes including TDP1 were identified as targets of miR-211. In contrast, TDP1 suppressed DNA damage and platinum chemosensitivity. Moreover, the miR-211 level in tissues was shown to be associated with the good outcome of neoadjuvant chemotherapy and negatively correlated with the expression of TDP1. Conclusively, we demonstrated that miR-211 improves the prognosis of ovarian cancer patients by enhancing the chemosensitivity of cancer cells to platinum via inhibiting DDR gene expression, which provides an essential basis to identify novel treatment targets to block DDR effectively and improve chemosensitivity in ovarian cancer.