Salvianolic acid B‐induced microRNA‐152 inhibits liver fibrosis by attenuating DNMT1‐mediated Patched1 methylation

Journal of Cellular and Molecular Medicine

Fujun Yu⁴  Zhongqiu Lu¹  Bicheng Chen²  Xiaoli Wu³  Peihong Dong⁴ 

[1]Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

[2]Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

[3]Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

[4]Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

关键词: microRNA‐152;    hepatic stellate cells;    DNA methylation;    Patched1;    DNA methyltransferase;   

DOI  :  10.1111/jcmm.12655

来源: Wiley

【 摘 要 】

Abstract

Epithelial-mesenchymal transition (EMT) was reported to be involved in the activation of hepatic stellate cells (HSCs), contributing to the development of liver fibrosis. Epithelial-mesenchymal transition can be promoted by the Hedgehog (Hh) pathway. Patched1 (PTCH1), a negative regulatory factor of the Hh signalling pathway, was down-regulated during liver fibrosis and associated with its hypermethylation status. MicroRNAs (miRNAs) are reported to play a critical role in the control of various HSCs functions. However, miRNA-mediated epigenetic regulations in EMT during liver fibrosis are seldom studied. In this study, Salvianolic acid B (Sal B) suppressed the activation of HSCs in CCl₄-treated mice and mouse primary HSCs, 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 PTCH1 was associated with decreased DNA methylation level after Sal B treatment. Accordingly, DNA methyltransferase 1 (DNMT1) was attenuated by Sal B in vivo and in vitro. The knockdown of DNMT1 in Sal B-treated HSCs enhanced PTCH1 expression and its demethylation level. Interestingly, increased miR-152 in Sal B-treated cells was responsible for the hypomethylation of PTCH1 by Sal B. As confirmed by the luciferase activity assay, DNMT1 was a direct target of miR-152. Further studies showed that the miR-152 inhibitor reversed Sal B-mediated PTCH1 up-regulation and DNMT1 down-regulation. Collectively, miR-152 induced by Sal B, contributed to DNMT1 down-regulation and epigenetically regulated PTCH1, resulting in the inhibition of EMT in liver fibrosis.

【 授权许可】

CC BY   
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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