title: MeCP2 silencing of LncRNA H19 controls hepatic stellate cell proliferation by targeting IGF1R.
abstract: Methyl-CpG-binding protein 2 (MeCP2) plays a key role in liver fibrosis. However, the potential mechanism of MeCP2 in liver fibrosis remains unclear. Early reports suggest that LncRNA H19 is important epigenetic regulator with critical roles in cell proliferation, but its role in hepatic fibrosis remains elusive. Sprague-Dawley rats liver fibrosis was generated by 12-weeks treatment with CCl4 intraperitoneal injection. HSC-T6 cells were used in vitro study. The expression levels of MeCP2, H19, IGF1R, α-SMA, and Col1A1 were estimated by Western blotting, qRT-PCR and Immunohistochemistry. HSC-T6 cells were transfected with MeCP2-siRNA, pEGF-C1-MeCP2, pEX-3-H19, and H19-siRNA. Finally, cell proliferation ability was assessed by the MTT assay. Here, we found that H19 was significantly down-regulated in HSCs and fibrosis tissues, and an opposite pattern is observed for MeCP2 and IGF1R. Silencing of MeCP2 blocked HSCs proliferation. Knockdown of MeCP2 elevated H19 expression in activated HSCs, and over-expression of MeCP2 inhibited H19 expression in activated HSCs. Moreover, we investigated the effect of H19 on IGF1R expression. Overexpression of H19 in HSCs repressed the expression of IGF1R, and an opposite pattern is observed for H19 silenced. In addition, we reported that overexpression of H19 inhibited the TGF-β1-induced proliferation of HSCs. Furthermore, MeCP2 negative regulation of H19 by targeting the protein IGF1R. Taken together, these results demonstrated that MeCP2 silencing of H19 can alter the IGF1R overexpression, thus contributing to HSCs proliferation. These data could suggest the development of combination therapies that target the MeCP2.
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liu
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Scientific, The Second Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: zydengsy@163.com.
authors.forename: Zi-Yu
authors.initials: ZY
authors.lastname: Deng
authors.affiliation: School of pharmacy, Anhui Medical University, Hefei, 230032, China. Electronic address: yncs01@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D002251:Carbon Tetrachloride; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D051783:Methyl-CpG-Binding Protein 2; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; C094335:H19 long non-coding RNA; C497394:Mecp2 protein, rat; C498862:Acta2 protein, rat
keywords: Epigenetic; H19; Hepatic fibrosis; Hepatic stellate cells; IGF1R; Methyl-CpG-binding protein 2