Role of miR-195 in Chemo-Resistant Ovarian Cancer

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Abstract Recurrence with drug resistance phenotype is frequent in high-grade serous ovarian cancer (HGSOC), the deadliest among gynecologic malignancies. However, molecular machineries responsible for recurrence and resistant phenotype in HGSOC are still evolving and urgently needed to overcome the therapeutic resistance and poor prognosis. In this context, establishing microRNA-195 (miR-195) as a critical molecule regulating drug resistance in HGSOC is significant. We recently reported that miR‐195 is under‐expressed in HGSOC, targets MICU1, and that its ectopic expression significantly reduces the clonal growth, migration, and invasion of ovarian cancer cells. Using a mouse model of ovarian cancer, we reported that miR-195 re-expression significantly reduces tumor growth, increases tumor doubling times, and enhances the overall survival of the tumor-bearing mouse. However, the role of miR-195 in drug resistance of HGSOC has not been elucidated. Interestingly, our in-silico analyses reveal that miR-195 can target WNT7A, a key ligand for the Wnt/β-catenin singling, which is upregulated in HGSOC and not detected in normal ovaries. Wnt/β-catenin singling in ovarian cancer is associated with stem-like properties in cancer cells with drug-resistant phenotype. Furthermore, we demonstrate in our preliminary data that miR-195 negatively regulates in Wnt/β-catenin signaling pathway in HGSOC cells. Based on these results, we hypothesize that the under-expression of miR-195 in HGSOC is responsible for WNT7A upregulation and evolution of the drug resistance phenotype. We will use specific aims below to test the hypothesis and accomplish overall objectives; Aim 1: Investigating the role of miR-195 expression in drug-resistant ovarian cancer. Aim 2: Evaluate the effect of miR-195 on metastasis and drug sensitivity in an ovarian cancer model using auroliposome mediated miR-195 delivery system. Successful completion of the project will establish miR-195 as a regulator of drug resistance in HGSOC and a potentially translatable strategy to overcome it either by miR-195 delivery or by targeting the WNT7A to inhibit the WNT/β- catenin pathway.