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丙泊酚通过调节 microRNA-374a/叉头框 O1 信号轴抑制卵巢癌细胞的增殖和顺铂耐药性。

Propofol inhibits proliferation and cisplatin resistance in ovarian cancer cells through regulating the microRNA‑374a/forkhead box O1 signaling axis.

机构信息

Department of Anesthesiology, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330003, P.R. China.

Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.

出版信息

Mol Med Rep. 2020 Mar;21(3):1471-1480. doi: 10.3892/mmr.2020.10943. Epub 2020 Jan 16.

Abstract

Ovarian cancer is a prominent disease that demonstrates high incidence rates in women and often presents multidrug resistance. Propofol has been demonstrated to suppress the malignancy of various types of human cancer; however, the underlying molecular mechanisms of propofol in ovarian cancer remain largely unknown. The present study aimed to investigate whether and how propofol inhibits proliferation and cisplatin (DDP) resistance in ovarian cancer cells. Ovarian cancer cell viability was assessed by the Cell Counting kit‑8 assay; apoptosis and cell cycle progression were determined by flow cytometry; the relative expression levels of microRNA (miR)‑374a and forkhead box O1 (FOXO1) were analyzed using reverse transcription‑quantitative PCR; the binding ability of miR‑374a to FOXO1 was assessed by the dual‑luciferase reporter assay; cellular sensitivity to DDP was detected using the MTT assay; and finally, the protein expression levels of FOXO1, p27, and Bcl‑2‑like‑protein 11 (Bim) were analyzed by western blotting. Propofol reduced viability, promoted apoptosis and decreased miR‑374a expression levels in A2780 cells. In addition, the viability of A2780/DDP cells in the propofol + DDP treatment group was significantly inhibited, and the apoptotic rate was increased. In addition, miR‑374a overexpression increased cell viability and the proportion of cells in the S phase, and decreased the proportion of cells in the G0/G1 phase. Conversely, genetic knockdown of miR‑374a exerted the opposite effects on cell viability and cell cycle progression. Moreover, miR‑374a was demonstrated to bind to FOXO1. Propofol promoted the expression of FOXO1, p27 and Bim, induced cell cycle arrest and decreased ovarian cancer cell viability. In addition, treatment with propofol and DDP regulated FOXO1 and increased apoptosis of ovarian cancer cells. In conclusion, propofol downregulated miR‑374a and modulated the FOXO1 pathway to reduce proliferation and DDP resistance in ovarian cancer cells.

摘要

卵巢癌是一种发病率较高的妇科恶性肿瘤,常表现出多药耐药性。已有研究表明,异丙酚可抑制多种人类癌症的恶性程度;然而,异丙酚在卵巢癌中的作用机制尚不清楚。本研究旨在探讨异丙酚是否以及如何抑制卵巢癌细胞的增殖和顺铂(DDP)耐药性。采用细胞计数试剂盒-8 法检测卵巢癌细胞活力;通过流式细胞术检测细胞凋亡和细胞周期进程;采用逆转录-定量 PCR 分析微小 RNA(miR)-374a 和叉头框 O1(FOXO1)的相对表达水平;采用双荧光素酶报告基因检测 miR-374a 与 FOXO1 的结合能力;采用 MTT 法检测细胞对 DDP 的敏感性;最后,采用 Western blot 法分析 FOXO1、p27 和 Bcl-2 样蛋白 11(Bim)的蛋白表达水平。结果表明,异丙酚降低了 A2780 细胞的活力,促进了细胞凋亡,降低了 miR-374a 的表达水平。此外,在异丙酚+DDP 处理组中,A2780/DDP 细胞的活力明显受到抑制,细胞凋亡率增加。此外,miR-374a 过表达增加了细胞活力和 S 期细胞比例,降低了 G0/G1 期细胞比例。相反,miR-374a 的基因敲低对细胞活力和细胞周期进程产生了相反的影响。此外,miR-374a 被证明与 FOXO1 结合。异丙酚促进 FOXO1、p27 和 Bim 的表达,诱导细胞周期停滞,降低卵巢癌细胞活力。此外,异丙酚和 DDP 处理调节 FOXO1 并增加卵巢癌细胞的凋亡。综上所述,异丙酚下调 miR-374a 并调节 FOXO1 通路,从而降低卵巢癌细胞的增殖和 DDP 耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abd1/7003056/6a56d5d98ebf/MMR-21-03-1471-g00.jpg

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