title: MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression.
abstract: Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.
authors.affiliation: Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Hyun
authors.affiliation: Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.
authors.forename: Sihyung
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea.
authors.forename: Kummara Madhusudana
authors.initials: KM
authors.lastname: Rao
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea.
authors.forename: Ildoo
authors.initials: I
authors.lastname: Chung
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea.
authors.forename: Chang-Sik
authors.initials: CS
authors.lastname: Ha
authors.affiliation: Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.|Department of Biological Sciences, College of Natural Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 46241, Korea.
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, College of Engineering, The University of Akron, Akron, Ohio 44685-0302, USA.
authors.forename: Yang H
authors.initials: YH
authors.lastname: Yun
authors.affiliation: Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea.|Department of Biological Sciences, College of Natural Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 46241, Korea.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D001483:Base Sequence; D002251:Carbon Tetrachloride; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002794:Choline; D002908:Chronic Disease; D015536:Down-Regulation; D005001:Ethionine; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008715:Methionine; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000072086:Smoothened Receptor; D051996:Transcription Factor RelA / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; C526012:MIRN378 microRNA, human; C546119:MIRN378 microRNA, mouse; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D051996:Transcription Factor RelA; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D008715:Methionine; D002251:Carbon Tetrachloride; D002794:Choline; D005001:Ethionine