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miR-30a-5p/CHD1 轴通过抑制 Wnt/β-catenin 通路增强卵巢癌细胞对顺铂的敏感性。

MiR-30a-5p/CHD1 axis enhances cisplatin sensitivity of ovarian cancer cells via inactivating the Wnt/β-catenin pathway.

机构信息

Department of Gynecology 1, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University.

Department of Biochemistry and Molecular Biology, Shanxi Medical University.

出版信息

Anticancer Drugs. 2022 Nov 1;33(10):989-998. doi: 10.1097/CAD.0000000000001397. Epub 2022 Sep 29.

Abstract

Oovarian cancer is a common lethal gynecological malignancy with a high occurrence and dismal prognosis on account of its drug resistance. MicroRNAs (miRNAs) are widely involved in the chemotherapy resistance of tumors, including miR-30a-5p. Herein, we probed the functional role and molecular mechanism of miR-30a-5p in the chemoresistance of ovarian cancer. We enrolled 48 ovarian cancer patients in this study. Statistical analysis and a series of experiments including quantitative reverse transcription polymerase chain reaction, western blot, methyl thiazolyl tetrazolium assay, colony formation assay, flow cytometry analysis, Transwell assay, luciferase reporter assay, RNA pull-down assay and TOP/FOP flash assay were explored in the study. Animal experiments were performed to verify the role of miR-30a-5p in vivo . In our study, miR-30a-5p showed a prominently low level in ovarian cancer tissues and cells. Importantly, its expression in cisplatin-resistant cell lines was more downregulated than in cisplatin-sensitive ones. Additionally, miR-30a-5p overexpression inhibited proliferative, migratory and invasive abilities of ovarian cancer cells while enhancing cell apoptosis and improving cell sensitivity to cisplatin in ovarian cancer. Further, miR-30a-5p targeted to chromodomain helicase DNA binding protein 1 (CHD1) and inhibited the expression of CHD1 in ovarian cancer. Moreover, rescue experiments manifested that miR-30a-5p weakened cisplatin resistance and the cellular process of ovarian cancer by mediating CHD1. Besides, miR-30a-5p regulated CHD1 expression to suppress Wnt/β-catenin signaling in ovarian cancer. The findings were verified by in vivo experiments. This article elucidated that miR-30a-5p/CHD1 axis inhibited the cellular process and enhanced cisplatin sensitivity of ovarian cancer cells through the Wnt/β-catenin pathway, which may provide a useful direction for the targeted chemotherapy of ovarian cancer.

摘要

卵巢癌是一种常见的致命妇科恶性肿瘤,由于其耐药性,其发病率和预后均较差。microRNAs (miRNAs) 广泛参与肿瘤的化疗耐药性,包括 miR-30a-5p。在此,我们研究了 miR-30a-5p 在卵巢癌化疗耐药性中的功能作用和分子机制。本研究纳入了 48 名卵巢癌患者。通过定量逆转录聚合酶链反应、western blot、噻唑蓝比色法、集落形成实验、流式细胞术分析、Transwell 实验、荧光素酶报告基因实验、RNA 下拉实验和 TOP/FOP flash 实验进行统计分析和一系列实验。通过动物实验验证 miR-30a-5p 在体内的作用。在本研究中,miR-30a-5p 在卵巢癌组织和细胞中表达水平明显降低。重要的是,其在顺铂耐药细胞系中的表达水平较顺铂敏感细胞系更低。此外,miR-30a-5p 过表达抑制卵巢癌细胞的增殖、迁移和侵袭能力,同时促进细胞凋亡,提高细胞对顺铂的敏感性。进一步的研究表明,miR-30a-5p 靶向于染色质解旋酶 DNA 结合蛋白 1 (CHD1),并抑制卵巢癌中 CHD1 的表达。此外,通过挽救实验表明,miR-30a-5p 通过调节 CHD1 来减弱卵巢癌的顺铂耐药性和细胞过程。此外,miR-30a-5p 调节 CHD1 的表达来抑制卵巢癌中的 Wnt/β-catenin 信号通路。体内实验验证了这些发现。本文阐明了 miR-30a-5p/CHD1 轴通过 Wnt/β-catenin 通路抑制卵巢癌细胞的细胞过程并增强其对顺铂的敏感性,这可能为卵巢癌的靶向化疗提供了一个有用的方向。

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