title: Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis.
abstract: 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-β1 (TGF-β1) stimulation in dose and time-dependent manner. Enforced expression of MEG3 in LX-2 cells inhibited TGF-β1-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-β1-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-β1-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.
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Bao-Ming
authors.initials: BM
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Feng-Yun
authors.initials: FY
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Lv
authors.affiliation: School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China. Electronic address: heyongR99@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
keywords: Liver fibrosis; MEG3; Methylation; lncRNAs; p53