Gut Liver.  2017 Jan;11(1):102-111. 10.5009/gnl15566.

Elk-3 Contributes to the Progression of Liver Fibrosis by Regulating the Epithelial-Mesenchymal Transition

Affiliations
  • 1The Catholic University Liver Research Center & WHO Collaborating Center of Viral Hepatitis, The Catholic University of Korea College of Medicine, Seoul, Korea. yoonsk@catholic.ac.kr
  • 2Molecular Medicine Research Center, Chifeng University School of Medical Science, Chifeng, China.

Abstract

BACKGROUND/AIMS
The role of Elk-3 in the epithelial-mesenchymal transition (EMT) during liver fibrogenesis remains unclear. Here, we determined the expression of Elk-3 in in vitro and in vivo models 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 vitro EMT 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.

Keyword

Epithelial-mesenchymal transition; Elk-3; Liver cirrhosis; Early growth response-1; MAPK pathway

MeSH Terms

Actins/metabolism
Animals
Blotting, Western
Cadherins/metabolism
Carbon Tetrachloride/toxicity
Cdh1 Proteins/metabolism
Cell Line
Disease Models, Animal
Early Growth Response Protein 1/*metabolism
Epithelial-Mesenchymal Transition/drug effects/*genetics
Gene Knockdown Techniques
Hepatocytes/drug effects/*metabolism
Humans
Liver Cirrhosis/*genetics/metabolism
Mice
Mitogen-Activated Protein Kinases
Piperazines/pharmacology
Proto-Oncogene Proteins c-ets/*genetics/metabolism
Pyrazoles/pharmacology
RNA, Small Interfering
Signal Transduction
Transforming Growth Factor beta1/toxicity
Vimentin/metabolism
Actins
Cadherins
Cdh1 Proteins
Early Growth Response Protein 1
Piperazines
Proto-Oncogene Proteins c-ets
Pyrazoles
RNA, Small Interfering
Transforming Growth Factor beta1
Vimentin
Carbon Tetrachloride
Mitogen-Activated Protein Kinases
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