title: miR-181a mediates TGF-β-induced hepatocyte EMT and is dysregulated in cirrhosis and hepatocellular cancer.
abstract: OBJECTIVE
  Epithelial-mesenchymal transition (EMT) has been implicated in the processes of embryogenesis, tissue fibrosis and carcinogenesis. Transforming growth factor-β (TGF-β) has been identified as a key driver of EMT and plays a key role in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC). The aim was to identify microRNA (miR) expression in TGF-β-induced hepatocyte EMT.
  
  
  METHODS
  We treated a human hepatocyte cell line PH5CH8 with TGF-β to induce an EMT-like change in phenotype and then identified dysregulated miRs using TaqMan Low Density Arrays. MiR expression was altered using miR-181a mimic and inhibitor in the same system and gene changes were identified using TaqMan gene arrays. MiR-181a gene expression was measured in human and mouse cirrhotic or HCC liver tissue samples. Gene changes were identified in rAAV-miR-181a-expressing mouse livers using TaqMan gene arrays.
  
  
  RESULTS
  We identified miR-181a as a miR that was significantly up-regulated in response to TGF-β treatment. Over-expression of a miR-181a mimic induced an in vitro EMT-like change with a phenotype similar to that seen with TGF-β treatment alone and was reversed using a miR-181a inhibitor. MiR-181a was shown to be up-regulated in experimental and human cirrhotic and HCC tissue. Mouse livers expressing rAAV-miR-181a showed genetic changes associated with TGF-β signalling and EMT.
  
  
  CONCLUSIONS
  MiR-181a had a direct effect in inducing hepatocyte EMT and was able to replace TGF-β-induced effects in vitro. MiR-181a was over-expressed in cirrhosis and HCC and is likely to play a role in disease pathogenesis.
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brockhausen
authors.forename: Szun S
authors.initials: SS
authors.lastname: Tay
authors.forename: Candice A
authors.initials: CA
authors.lastname: Grzelak
authors.forename: Patrick
authors.initials: P
authors.lastname: Bertolino
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.forename: William M
authors.initials: WM
authors.lastname: d'Avigdor
authors.forename: Narcy
authors.initials: N
authors.lastname: Teoh
authors.forename: Sharon
authors.initials: S
authors.lastname: Pok
authors.forename: Nick
authors.initials: N
authors.lastname: Shackel
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
authors.forename: Mathew
authors.initials: M
authors.lastname: Vadas
authors.forename: Geoff W
authors.initials: GW
authors.lastname: McCaughan
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
chemical_list: C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta
keywords: EMT; TGF-β; cirrhosis; hepatocellular carcinoma; hepatocyte; microRNA