title: MicroRNA-101 suppresses liver fibrosis by targeting the TGFβ signalling pathway.
abstract: Transforming growth factor-β (TGFβ) is crucial for liver fibrogenesis and the blunting of TGFβ signalling in hepatic stellate cells (HSCs) or hepatocytes can effectively inhibit liver fibrosis. microRNAs (miRNAs) have emerged as key regulators in modulating TGFβ signalling and liver fibrogenesis. However, the regulation of TGFβ 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 (CCl4 )-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 CCl4 -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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, People's Republic of China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Tu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Jingcheng
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuhua
authors.initials: S
authors.lastname: Zhao
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Zheng
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Zang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D016415:Sequence Alignment; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; C581233:MIRN101 microRNA, mouse; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
keywords: KLF6; TGFβ signalling; TβRI; hepatic stellate cell; hepatocyte; liver fibrosis; miR-101