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

Abstract

Background/AimsThe 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.MethodsWe 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.ResultsThe 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.ConclusionsElk-3 contributes to the progression of liver fibrosis by modulating the EMT via the regulation of Egr-1 under MAPK signaling.

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

“…Mutations in ELK3 disrupt vasculogenesis, angiogenesis and wound healing in mice during development and in adulthood (24,25). In addition, our previous study demonstrated that ELK3 contributes to epithelial-mesenchymal transition (EMT) of mouse hepatocytes by regulating egr-1 (26). EMT, a process whereby epithelial cells reduce their intercellular adhesions and gain mesenchymal properties, is a critical event in the process of cancer invasion and metastasis (27,28).…”

“…In a previous study, we demonstrated that ELK3 expression plays an important role in the process of EMT during liver fibrogenesis (26). Acquiring cell motility is necessary for the transition from an epithelial to a mesenchymal phenotype (27,28).…”

The Potential Role of Elk-3/Egr-1 Signaling Pathway in the Epithelial-Mesenchymal Transition during Liver Fibrosis

“…Li et al 8. investigated novel molecular mechanisms involved in the EMT of hepatocytes and liver fibrosis.…”

“…However, to the best of our knowledge, there have not been any studies investigating the role of Elk-3 and Egr-1 during EMT of hepatocyte in liver fibrosis. Li et al 8. demonstrated that the expression levels of Elk-3 and Egr-1 were significantly increased during TGF-β1-induced EMT of hepatocytes, in both the CCl 4 -induced mouse liver fibrotic tissues and in the human liver cirrhotic tissues.…”

“…Moreover, Elk-3 expression was regulated by p38 MAPK phosphorylation during EMT. Therefore, the study by Li et al 8. suggested Elk-3/Egr-1 MAPK signaling as a novel molecular pathway in the progression of liver fibrosis via the regulation of hepatocyte EMT.…”