Department of Obstetrics and Gynecology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710002, P.R. China.
Department of Gynecology, Shangluo Central Hospital, Shangluo, Shaanxi 726000, P.R. China.
Oncol Rep. 2018 Apr;39(4):1649-1657. doi: 10.3892/or.2018.6259. Epub 2018 Feb 12.
Drug resistance remains a large obstacle for the treatment of ovarian cancer. miRNAs have been reported to be involved in cisplatin (CDDP) resistance in ovarian cancer. The aim of the present study was to investigate the function and mechanism of miR-199a-3p in the CDDP resistance in ovarian cancer. We found that miR-199a-3p was significantly downregulated in chemoresistant ovarian cancer tissues, as well as CDDP-resistant SKOV3/CDDP cells, compared to chemosensitive carcinomas and SKOV3 cells. Restoration of miR-199a-3p in SKOV3/CDDP cells reduced cell proliferation, G1 phase cell cycle arrest, cell invasion, and increased cell apoptosis, resulting in enhanced CDDP sensitivity, while miR-199a-3p inhibition resulted in the opposite effects. Luciferase reporter assay showed that integrin β8 (ITGB8), one of the integrins that is involved in the regulation of cell cycle and motility, was a direct target of miR-199a-3p. Overexpression of miR-199a-3p downregulated ITGB8 expression via binding to its 3'-UTR. In addition, overexpression of ITGB8 restored CDDP resistance inhibited by miR-199a-3p. Moreover, orthotopic ovarian cancer mouse model showed that miR‑199a-3p enhanced CDDP sensitivity of ovarian cancer in vivo. Therefore, our results indicate that miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression, and miR-199a-3p may serve as a therapeutic target for the treatment of ovarian cancer patients with CDDP-resistance.
耐药性仍然是卵巢癌治疗的一大障碍。有研究报道 miRNAs 参与了卵巢癌对顺铂（CDDP）的耐药性。本研究旨在探讨 miR-199a-3p 在卵巢癌 CDDP 耐药中的作用及其机制。我们发现，与化疗敏感型癌和 SKOV3 细胞相比，耐药性卵巢癌组织和 CDDP 耐药性 SKOV3/CDDP 细胞中 miR-199a-3p 表达显著下调。在 SKOV3/CDDP 细胞中恢复 miR-199a-3p 的表达可降低细胞增殖、G1 期细胞周期阻滞、细胞侵袭，并增加细胞凋亡，从而增强 CDDP 敏感性，而 miR-199a-3p 抑制则产生相反的效果。荧光素酶报告基因检测显示，整合素β8（ITGB8）是参与细胞周期和运动调节的整合素之一，是 miR-199a-3p 的直接靶标。miR-199a-3p 的过表达通过与其 3'-UTR 结合下调 ITGB8 表达。此外，过表达 ITGB8 可恢复 miR-199a-3p 抑制的 CDDP 耐药性。此外，卵巢癌原位小鼠模型表明，miR-199a-3p 在体内增强了卵巢癌对 CDDP 的敏感性。因此，我们的研究结果表明，miR-199a-3p 通过下调 ITGB8 表达增强卵巢癌细胞对 CDDP 的敏感性，miR-199a-3p 可能成为治疗 CDDP 耐药性卵巢癌患者的治疗靶点。
