MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity
MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity
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MicroRNA-101 通过 EZH2 下调和增加细胞抑制剂敏感性抑制人肝细胞癌进展
DOI：
10.1016/j.jhep.2013.10.028
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发表时间：
2014-03-01
影响因子：
25.7
通讯作者：
Cicinnati, Vito R.
中科院分区：
文献类型：
--
作者：
Xu, Leibo;Beckebaum, Susanne;Cicinnati, Vito R.
背景和目标：癌基因polycomb group protein enhancer of zeste homolog 2（EZH 2）被认为是肿瘤抑制microRNA-101（miR-101）的靶基因。本研究旨在探讨miR-101和EZH 2在人肝细胞癌（HCC）中的功能作用。方法：采用实时荧光定量PCR（real-time PCR）检测99例HCC患者肿瘤组织和7株肝癌细胞株中miR-101和EZH 2的表达。采用荧光素酶报告基因试验验证EZH 2是否代表miR-101的靶基因。结果：miR-101在大多数肝癌组织和所有细胞系中表达显著下调，而EZH 2在大多数肝癌组织和所有细胞系中显著过表达。miR-101和EZH 2的表达水平呈负相关。荧光素酶分析结果证实EZH 2是miR-101的直接靶基因，其负调控HCC中EZH 2的表达。miR-101的异位过表达在体外显著抑制增殖、侵袭、集落形成以及细胞周期进程，并且在体内抑制致瘤性。结论：肿瘤抑制剂miR-101通过直接靶向EZH 2癌基因，抑制肝癌细胞的生长，提高肝癌细胞对化疗药物的敏感性。我们的研究结果为肝癌发生的分子机制提供了重要的见解，并可能对肝癌新靶向治疗的发展具有临床意义。(C)2013年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Oncogene polycomb group protein enhancer of zeste homolog 2 (EZH2) has been proposed to be a target gene of putative tumor suppressor microRNA-101 (miR-101). The aim of our study was to investigate the functional role of both miR-101 and EZH2 in human hepatocellular carcinoma (HCC).Methods: MiR-101 and EZH2 expressions were evaluated in tumor tissues of 99 HCC patients and 7 liver cancer cell lines by real-time PCR. Luciferase reporter assay was employed to validate whether EZH2 represents a target gene of miR-101. The effect of miR-101 on HCC growth as well as programmed cell death was studied in vitro and in vivo.Results: MiR-101 expression was significantly downregulated in most of HCC tissues and all cell lines, whereas EZH2 was significantly overexpressed in most of HCC tissues and all cell lines. There was a negative correlation between expression levels of miR-101 and EZH2. Luciferase assay results confirmed EZH2 as a direct target gene of miR-101, which negatively regulates EZH2 expression in HCC. Ectopic overexpression of miR-101 dramatically repressed proliferation, invasion, colony formation as well as cell cycle progression in vitro and suppressed tumorigenicity in vivo. Furthermore, miR-101 inhibited autophagy and synergized with either doxorubicin or fluorouracil to induce apoptosis in tumor cells.Conclusion: Tumor suppressor miR-101 represses HCC progression through directly targeting EZH2 oncogene and sensitizes liver cancer cells to chemotherapeutic treatment. Our findings provide significant insights into molecular mechanisms of hepatocarcinogenesis and may have clinical relevance for the development of novel targeted therapies for HCC. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.