Department of Obstetrics and Gynecology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, 200011, Shanghai, P.R. China.
Cancer Gene Ther. 2021 Aug;28(7-8):785-798. doi: 10.1038/s41417-020-0195-6. Epub 2020 Jul 7.
Cisplatin (DDP)-based strategies are the first-line treatment for cancers; however, resistance to DDP remains a major obstacle to cancer treatment. The current study set out to investigate the effects of microRNA-181c (miR-181c) on the resistance of ovarian cancer cells to DDP. Ovarian cancer-associated miRs as well as the target messenger RNAs were screened using microarray-based analysis followed by determining the expression patterns of miR-181c and mesoderm-specific transcript (MEST) in ovarian cancer tissues with RT-qPCR and Western blot analysis. Subsequently, dual-luciferase reporter gene assay was performed to confirm the targeting relation between miR-181c and MEST. Through gain- or loss-of-function experiments, the study explored the mechanism by which miR-181 regulated MEST to influence the resistance of ovarian cancer cells to DDP via the Wnt/β-catenin signaling pathway. Afterwards, extracellular vesicles (EVs) were isolated from bone marrow stromal cells (BMSCs) and co-cultured with ovarian cancer cells to further investigate the effects of overexpressed miR-181 delivered by BMSCs-derived EVs on ovarian cancer cell resistance to DDP. miR-181c was significantly downregulated, while MEST was up-regulated in ovarian cancer. miR-181c was verified to specifically bind to MEST. Overexpressed miR-181c depleted the expression of MEST to attenuate the resistance of ovarian cancer cells to DDP by inactivating the Wnt/β-catenin signaling pathway. Furthermore, the delivery of overexpressed miR-181c by BMSCs-derived EVs was found to suppress the resistance of ovarian cancer cells to DDP. These findings demonstrate that miR-181c delivered by BMSCs-derived EVs down-regulates MEST, to inactivate the Wnt/β-catenin signaling pathway, thus repressing the resistance of ovarian cancer cells to DDP.
顺铂（DDP）为基础的策略是癌症的一线治疗方法；然而，对 DDP 的耐药性仍然是癌症治疗的主要障碍。本研究旨在探讨 microRNA-181c（miR-181c）对卵巢癌细胞对 DDP 耐药性的影响。采用基于微阵列的分析筛选卵巢癌相关 miR 和靶信使 RNA，然后采用 RT-qPCR 和 Western blot 分析确定卵巢癌组织中 miR-181c 和中胚层特异性转录物（MEST）的表达模式。随后，通过双荧光素酶报告基因检测证实 miR-181c 与 MEST 之间的靶向关系。通过增益或功能丧失实验，研究探讨了 miR-181 调节 MEST 影响卵巢癌细胞对 DDP 耐药性的机制，通过 Wnt/β-catenin 信号通路。之后，从骨髓基质细胞（BMSCs）中分离出细胞外囊泡（EVs）并与卵巢癌细胞共培养，进一步研究 BMSCs 衍生的 EVs 过表达的 miR-181 对卵巢癌细胞对 DDP 耐药性的影响。miR-181c 在卵巢癌中显著下调，而 MEST 上调。miR-181c 被证实特异性结合 MEST。过表达的 miR-181c 耗尽了 MEST 的表达，通过使 Wnt/β-catenin 信号通路失活来减轻卵巢癌细胞对 DDP 的耐药性。此外，发现 BMSCs 衍生的 EVs 传递过表达的 miR-181c 可抑制卵巢癌细胞对 DDP 的耐药性。这些发现表明，BMSCs 衍生的 EVs 传递的 miR-181c 下调 MEST，使 Wnt/β-catenin 信号通路失活，从而抑制卵巢癌细胞对 DDP 的耐药性。
