title: miR-30c and miR-193 are a part of the TGF-β-dependent regulatory network controlling extracellular matrix genes in liver fibrosis.
abstract: OBJECTIVE
  MicroRNAs (miRNAs) have recently emerged as novel regulators in liver fibrosis. miR-30c and miR-193 are involved in fibrotic remodeling processes and cancer development, respectively. This study aimed to explore the role of miR-30c and miR-193 in liver fibrosis.
  
  
  METHODS
  The regulation of miRNAs in carbon tetrachloride-induced liver fibrosis was analyzed by microarray. Expression patterns of miR-193 and miR-30c were further confirmed in fibrotic liver samples obtained from two murine models of hepatic fibrosis and human tissues. On a functional level, miRNA levels were analyzed in the context of transforming growth factor (TGF-β) mediated activation of hepatic stellate cells (HSCs). Finally, predicted targets were assessed for their roles in fibrosis by transfecting murine HSCs with miRNA mimics.
  
  
  RESULTS
  Microarray analysis in murine fibrotic livers revealed a panel of 44 dysregulated miRNAs. In addition to previously established miRNAs known to be regulated in liver fibrosis in a TGF-β-dependent manner (e.g., miR-29, miR-133), miR-193 and miR-30c were observed to be specifically downregulated not only in experimental hepatofibrogenesis but also in human liver fibrosis, while they showed a reciprocal expression pattern after recovery from liver fibrosis. Functional experiments confirmed the TGF-β-dependent downregulation of these respective new miRNAs in HSCs. Finally, we identified TGF-β2 and SNAIL1, important regulators of extracellular matrix, as potential target genes of miR-193 and miR-30 in liver fibrosis.
  
  
  CONCLUSIONS
  These results suggest that miR-30 and miR-193 are members of a network of miRNAs modifying the TGF-β-dependent regulation of extracellular matrix-related genes in HSCs in the manifestation and resolution of liver fibrosis.
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Sanchari
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Benz
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Vargas Cardenas
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
authors.affiliation: EA4483, Faculté de Médecine de Lille, Pole Recherche, Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pottier
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Alder
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Roderburg
authors.affiliation: Department of Medicine III, University of Aachen (RWTH), Aachen, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012372:ROC Curve; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; C546818:MIRN193 microRNA, human; C568257:MIRN193 microRNA, mouse; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride
keywords: hepatic stellate cells; liver fibrosis; miR-193; miR-30; microRANs; transforming growth factor beta