Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis
Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis
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长链非编码RNA MEG3对肝星状细胞活化和肝纤维化的抑制作用
DOI：
10.1016/j.bbadis.2014.08.015
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发表时间：
2014-11-01
影响因子：
6.2
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
He, Yong;Wu, Yu-ting;Li, Jun
长链非编码RNA（lncRNA）正越来越多地被认为是通过多种机制控制基本生物过程的主要参与者。母系表达基因3（MEG 3）是位于14 q32的印记基因，其编码与多种人类癌症相关的lncRNA。最近，MEG 3的甲基化依赖性下调已经在肝癌中被描述。然而，其在肝纤维化中的生物学功能作用仍不清楚。在我们的研究中，MEG 3水平显着降低四氯化碳诱导的小鼠肝纤维化模型和人类肝纤维化的实时定量PCR证明。此外，MEG 3的表达下调人肝星状细胞系LX-2细胞响应于转化生长因子-β 1（TGF-β 1）的刺激剂量和时间依赖性的方式。LX-2细胞中MEG 3的增强表达抑制了TGF-β 1诱导的细胞增殖，同时促进了细胞凋亡。此外，通过甲基化特异性PCR鉴定MEG 3启动子的超甲基化，并且通过用5-azadC或siRNA抑制TGF-β 1诱导的LX-2细胞中的DNA甲基转移酶1（DNMT 1）的甲基化来稳健地增加MEG 3表达。更重要的是，MEG 3的过表达可以激活p53并介导细胞色素c的释放，随后导致TGF-β 1处理的LX-2细胞中的caspase-3依赖性凋亡。这些发现表明MEG 3可能在星状细胞活化和肝纤维化进展中起重要作用，并作为肝纤维化的新的潜在治疗靶点。(C)2014爱思唯尔有限公司版权所有。
Long noncoding RNAs (lncRNAs) are being increasingly recognized as major players in governing fundamental biological processes through diverse mechanisms. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes a lncRNA correlated with several human cancers. Recently, the methylation-dependent downregulation of MEG3 has been described in liver cancers. However, its biological functional role in liver fibrosis remains unknown. In our study, MEG3 levels were remarkably decreased in CCl4-induced mouse liver fibrosis models and human fibrotic livers as demonstrated by real-time quantitative PCR. Moreover, the expression of MEG3 was downregulated in human hepatic stellate cell lines LX-2 cells in response to transforming growth factor-beta 1 (TGF-beta 1) stimulation in dose and time-dependent manner. Enforced expression of MEG3 in LX-2 cells inhibited TGF-beta 1-induced cell proliferation, while promoting cell apoptosis. In addition, hypermethylation of MEG3 promoter was identified by methylation-specific PCR and MEG3 expression was robustly increased by the inhibition of methylation with either 5-aza-2-deoxycytidine (5-azadC), or siRNA to DNA methyltransferase 1 (DNMT1) in TGF-beta 1-induced LX-2 cells. More importantly, overexpression of MEG3 could activate p53 and mediate cytochrome c release, subsequently leading to caspase-3-dependent apoptosis in TGF-beta 1-treated LX-2 cells. These findings suggested that MEG3 may play an important role in stellate cell activation and liver fibrosis progression and act as a novel potential therapeutic target for liver fibrosis. (C) 2014 Elsevier B.V. All rights reserved.