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MicroRNA ‐101 suppresses liver fibrosis by targeting the TGF β signalling pathway
Author(s) -
Tu Xiaolong,
Zhang Haiyan,
Zhang Jingcheng,
Zhao Shuhua,
Zheng Xiuxiu,
Zhang Zhengping,
Zhu Jie,
Chen Jiangning,
Dong Lei,
Zang Yuhui,
Zhang Junfeng
Publication year - 2014
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4373
Subject(s) - signalling , microrna , transforming growth factor , microbiology and biotechnology , chemistry , biology , biochemistry , gene
Transforming growth factor‐β ( TGF β) is crucial for liver fibrogenesis and the blunting of TGF β signalling in hepatic stellate cells ( HSCs ) or hepatocytes can effectively inhibit liver fibrosis. microRNAs ( miRNAs ) have emerged as key regulators in modulating TGF β signalling and liver fibrogenesis. However, the regulation of TGF β receptor I (TβRI) production by miRNA remains poorly understood. Here we demonstrate that the miR‐101 family members act as suppressors of TGFβ signalling by targeting TβRI and its transcriptional activator Kruppel‐like factor 6 (KLF6) during liver fibrogenesis. Using a mouse model of carbon tetrachloride (CCl 4 )‐induced liver fibrosis, we conducted a time‐course experiment and observed significant down‐regulation of miR‐101 in the fibrotic liver as well as in the activated HSCs and injured hepatocytes in the process of liver fibrosis. Meanwhile, up‐regulation of TβRI/KLF6 was observed in the fibrotic liver. Subsequent investigations validated that TβRI and KLF6 were direct targets of miR‐101. Lentivirus‐mediated ectopic expression of miR‐101 in liver greatly reduced CCl 4 ‐induced liver fibrosis, whereas intravenous administration of antisense miR‐101 oligonucleotides aggravated hepatic fibrogenesis. Mechanistic studies revealed that miR‐101 inhibited profibrogenic TGFβ signalling by suppressing TβRI expression in both HSCs and hepatocytes. Additionally, miR‐101 promoted the reversal of activated HSCs to a quiescent state, as indicated by suppression of proliferation and migration, loss of activation markers and gain of quiescent HSC‐specific markers. In hepatocytes, miR‐101 attenuated profibrogenic TGFβ signalling and suppressed the consequent up‐regulation of profibrogenic cytokines, as well as TGFβ‐induced hepatocyte apoptosis and the inhibition of cell proliferation. The pleiotropic roles of miR‐101 in hepatic fibrogenesis suggest that it could be a potential therapeutic target for liver fibrosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.