Role of miR-195 in Chemo-Resistant Ovarian Cancer

摘要 高级别浆液性卵巢癌(HGSOC)耐药表型复发是常见的 在妇科恶性肿瘤中是最致命的。然而，导致复发和死亡的分子机制 HGSOC的耐药表型仍在演变，迫切需要克服治疗耐药 预后不良。在此背景下，将microRNA-195(miR-195)确立为调节药物的关键分子 HGSOC的耐药性很大。我们最近报道了miR-195在HGSOC中表达不足，靶标 MICU1的异位表达显著降低了卵巢癌细胞的克隆生长、迁移和侵袭。 癌细胞。在卵巢癌小鼠模型上，我们报告了miR-195的重新表达显著 减少肿瘤生长，增加肿瘤倍增时间，并提高荷瘤患者的总体生存 老鼠。然而，miR-195在HGSOC耐药中的作用尚未阐明。 有趣的是，我们的电子分析表明，miR-195可以靶向Wnt7A，Wnt7A是Wnt/β-连接蛋白的关键配体 Singling，它在HGSOC中上调，在正常卵巢中检测不到。WnT/β-连环蛋白在卵巢中的表达 癌症与具有耐药表型的癌细胞中的干细胞特性有关。此外，我们 我们的初步数据表明，miR-195在Wnt/β-catenin信号通路中具有负性调节作用 HGSOC细胞。基于这些结果，我们推测miR-195在HGSOC中的低表达是 负责WNT7A的上调和耐药表型的进化。我们将使用特定的目标 以检验假设并实现总体目标；目标1：研究miR-195的作用 在耐药卵巢癌中的表达。目的2：评价miR-195对肿瘤转移和药物的影响 金脂质体介导的miR-195递送系统在卵巢癌模型中的敏感性。成功 该项目的完成将使miR-195成为HGSOC耐药的调节器，并有可能成为 可翻译的策略，以克服它，要么通过交付miR-195，要么通过靶向WNT7A来抑制WNT/β- 连环蛋白途径。

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.