Open AccessSalvianolic acid B‐induced micro RNA ‐152 inhibits liver fibrosis by attenuating DNMT 1‐mediated Patched1 methylation
Author(s) -
Yu Fujun,
Lu Zhongqiu,
Chen Bicheng,
Wu Xiaoli,
Dong Peihong,
Zheng Jianjian
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12655
Subject(s) - epithelial–mesenchymal transition , dnmt1 , dna methylation , chemistry , microbiology and biotechnology , cancer research , hepatic stellate cell , methylation , gene knockdown , microrna , methyltransferase , biology , downregulation and upregulation , endocrinology , gene expression , biochemistry , apoptosis , gene
Abstract Epithelial‐mesenchymal transition ( EMT ) was reported to be involved in the activation of hepatic stellate cells ( HSC s), contributing to the development of liver fibrosis. Epithelial‐mesenchymal transition can be promoted by the Hedgehog (Hh) pathway. Patched1 ( PTCH 1), a negative regulatory factor of the Hh signalling pathway, was down‐regulated during liver fibrosis and associated with its hypermethylation status. Micro RNA s (mi RNA s) are reported to play a critical role in the control of various HSC s functions. However, mi RNA ‐mediated epigenetic regulations in EMT during liver fibrosis are seldom studied. In this study, Salvianolic acid B (Sal B) suppressed the activation of HSC s in CC l 4 ‐treated mice and mouse primary HSC s, leading to inhibition of cell proliferation, type I collagen and alpha‐smooth muscle actin. We demonstrated that the antifibrotic effects caused by Sal B were, at least in part, via inhibition of EMT and the Hh pathway. In particular, up‐regulation of PTCH 1 was associated with decreased DNA methylation level after Sal B treatment. Accordingly, DNA methyltransferase 1 ( DNMT 1) was attenuated by Sal B in vivo and in vitro . The knockdown of DNMT 1 in Sal B‐treated HSC s enhanced PTCH 1 expression and its demethylation level. Interestingly, increased miR‐152 in Sal B‐treated cells was responsible for the hypomethylation of PTCH 1 by Sal B. As confirmed by the luciferase activity assay, DNMT 1 was a direct target of miR‐152. Further studies showed that the miR‐152 inhibitor reversed Sal B‐mediated PTCH 1 up‐regulation and DNMT 1 down‐regulation. Collectively, miR‐152 induced by Sal B, contributed to DNMT 1 down‐regulation and epigenetically regulated PTCH 1, resulting in the inhibition of EMT in liver fibrosis.