Wu Di-di, Li Xue-Song, Meng Xiao-Na, Yan Jing, Zong Zhi-Hong
Department of Biochemistry and Molecular Biology, College of Basic Medicine, China Medical University, Shenyang, 110013, People's Republic of China.
Tumour Biol. 2016 Aug;37(8):10499-506. doi: 10.1007/s13277-016-4944-y. Epub 2016 Feb 5.
Ovarian cancer is commonly treated with cisplatin and paclitaxel combination chemotherapy; however, ovarian cancer cells often develop resistance to these drugs. Increasingly, microRNAs (miRNAs) including miR-873 have been implicated in drug resistance in many cancers, but the role of miR-873 in ovarian cancer remains unknown. MTT cell viability assays revealed that the sensitivities of ovarian cancer lines to cisplatin and paclitaxel increased following transfection with miR-873 (P < 0.05). After predicting the miR-873 binding region in the 3'-untranslated region of ABCB1, dual-luciferase reporter assay confirmed this prediction. RT-PCR and Western blotting revealed that MDR1 expression was significantly downregulated after transfection with miR-873 and upregulated after transfection with anti-miR-873 at both mRNA and protein levels compared to negative controls (P < 0.05). Experiments in a mouse xenograft model confirmed that intratumoral administration of miR-873 could enhance the efficacy of cisplatin in inhibiting tumor growth in ovarian cancer in vivo (P < 0.05). ABCB1 overexpression reduced sensitivities of ovarian cancer lines OVCAR3 and A2780 to cisplatin and paclitaxel, which can be reversed by miR-873 mimic transfection (P < 0.05). In summary, we demonstrated that overexpression of miR-873 increased the sensitivity of ovarian cancer cells to cisplatin and paclitaxel by targeting MDR1 expression. Our findings suggest that combination therapies with chemotherapy agents and miR-873 may suppress drug resistance in ovarian cancer.
卵巢癌通常采用顺铂和紫杉醇联合化疗进行治疗；然而，卵巢癌细胞常常会对这些药物产生耐药性。越来越多的包括miR - 873在内的微小RNA（miRNA）已被证明与多种癌症的耐药性有关，但miR - 873在卵巢癌中的作用仍不清楚。MTT细胞活力测定显示，用miR - 873转染后，卵巢癌细胞系对顺铂和紫杉醇的敏感性增加（P < 0.05）。在预测了ABCB1的3' - 非翻译区中的miR - 873结合区域后，双荧光素酶报告基因测定证实了这一预测。RT - PCR和蛋白质印迹分析表明，与阴性对照相比，用miR - 873转染后，MDR1在mRNA和蛋白质水平上的表达均显著下调，而用抗miR - 873转染后则上调（P < 0.05）。小鼠异种移植模型实验证实，瘤内注射miR - 873可增强顺铂在体内抑制卵巢癌肿瘤生长的疗效（P < 0.05）。ABCB1的过表达降低了卵巢癌细胞系OVCAR3和A2780对顺铂和紫杉醇的敏感性，而miR - 873模拟物转染可逆转这种情况（P < 0.05）。总之，我们证明了miR - 873的过表达通过靶向MDR1的表达增加了卵巢癌细胞对顺铂和紫杉醇的敏感性。我们的研究结果表明，化疗药物与miR - 873的联合治疗可能会抑制卵巢癌的耐药性。
