Liu Jue, Zhang Xiaobo, Huang Yuliang, Zhang Qunfeng, Zhou Jianbin, Zhang Xiaodi, Wang Xiaoxu
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China.
Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Oncol Lett. 2019 Feb;17(2):1453-1460. doi: 10.3892/ol.2018.9745. Epub 2018 Nov 22.
Cisplatin is a first-line chemotherapy drug that is commonly used in the treatment of epithelial ovarian cancer (EOC). However, insensitivity to cisplatin markedly influences the outcomes of chemotherapy. MicroRNAs (miRNAs/miRs) have been demonstrated to modulate drug resistance in a number of types of cancer. The aim of the present study was to investigate the key miRNAs involved in modulating drug resistance in ovarian cancer cells. miR-200b and miR-200c were identified to be frequently deregulated in ovarian cancer. Upregulation of miR-200b and miR-200c promoted EOC cell death in the presence of cisplatin. Upregulation of miR-125b-5p significantly decreased tumor growth in combination with cisplatin in a mouse model. Significantly, miR-200b and miR-200c reversed cisplatin resistance by targeting DNA methyltransferases (DNMTs) (directly targeting DNMT3A/DNMT3B and indirectly targeting DNMT1 via specificity protein 1). These results indicate that miR-200b- and miR-200c-mediated regulation of DNMTs serves a crucial function in the cellular response to cisplatin. miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells and thus may have an impact on ovarian cancer therapy.
顺铂是一种一线化疗药物，常用于治疗上皮性卵巢癌（EOC）。然而，对顺铂不敏感会显著影响化疗效果。微小RNA（miRNA/miR）已被证明可调节多种癌症类型中的耐药性。本研究的目的是调查参与调节卵巢癌细胞耐药性的关键miRNA。已确定miR-200b和miR-200c在卵巢癌中经常失调。在存在顺铂的情况下，miR-200b和miR-200c的上调促进了EOC细胞死亡。在小鼠模型中，miR-125b-5p的上调与顺铂联合使用时显著降低了肿瘤生长。重要的是，miR-200b和miR-200c通过靶向DNA甲基转移酶（DNMT）逆转了顺铂耐药性（直接靶向DNMT3A/DNMT3B，并通过特异性蛋白1间接靶向DNMT1）。这些结果表明，miR-200b和miR-200c介导的DNMT调节在细胞对顺铂的反应中起关键作用。miR-200b和miR-200c介导的DNMT下调可能通过增加癌细胞的敏感性来提高化疗疗效，从而可能对卵巢癌治疗产生影响。
