title: Elk-3 Contributes to the Progression of Liver Fibrosis by Regulating the Epithelial-Mesenchymal Transition.
abstract: OBJECTIVE
  The role of Elk-3 in the epithelial-mesenchymal transition (EMT) during liver fibrogenesis remains unclear. Here, we determined the expression of Elk-3 inin vitroandin vivomodels and in human liver fibrotic tissues. We also investigated the molecular relationships among Elk-3, early growth response-1 (Egr-1), and the mitogen activated protein kinases (MAPK) pathway during EMT in hepatocytes.
  
  
  METHODS
  We established anin vitroEMT model in which normal mouse hepatocyte cell lines were treated with transforming growth factor (TGF)-β1 and a CCl₄-induced liver fibrosis model. Characteristics of EMT were determined by evaluating the expression levels of related markers. The expression of Elk-3 and its target Egr-1 were analyzed using Western blotting. Gene silencing of Elk-3 was performed using an siRNA knockdown system.
  
  
  RESULTS
  The expression levels of mesenchymal markers were increased during TGF-β1-induced EMT of hepatocytes. The expression levels of Elk-3 and Egr-1 were significantly (p<0.05) increased during the EMT of hepatocytes, in CCl₄-induced mouse liver fibrotic tissues, and in human liver cirrhotic tissues. Silencing of Elk-3 and inhibition of the Ras-Elk-3 pathway with an inhibitor suppressed the expression of EMT-related markers. Moreover, Elk-3 expression was regulated by p38 MAPK phosphorylation during EMT.
  
  
  CONCLUSIONS
  Elk-3 contributes to the progression of liver fibrosis by modulating the EMT via the regulation of Egr-1 under MAPK signaling.
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.|Molecular Medicine Research Center, Chifeng University School of Medical Science, Chifeng, China.
authors.forename: Tian Zhu
authors.initials: TZ
authors.lastname: Li
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Choi
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Eun Byul
authors.initials: EB
authors.lastname: Lee
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Joon Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea.
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D064200:Cdh1 Proteins / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010879:Piperazines / Q000494:pharmacology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000633:toxicity; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C086924:Elk3 protein, mouse; C577585:Fzr1 protein, mouse; D010879:Piperazines; D050783:Proto-Oncogene Proteins c-ets; D011720:Pyrazoles; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C527882:XRP44X compound; C544013:alpha-smooth muscle actin, mouse; D002251:Carbon Tetrachloride; D020928:Mitogen-Activated Protein Kinases
keywords: Early growth response-1; Elk-3; Epithelial-mesenchymal transition; Liver cirrhosis; MAPK pathway