Sorafenib Improves Liver Fibrosis by the Inhibition of TGF-β1-mediated EMT and Apoptosis in Mouse Hepatocytes

Epithelial–mesenchymal transition (EMT) is a dynamic cellular program in which polarized epithelial cells lose epithelial properties, undergo morphological changes and acquire mesenchymal characteristics. Aside from the essential role this transition plays in embryonic development, EMT has also been well studied in the context of physiological and pathological progression of an increasingly large number of human diseases, including liver fibrosis, cirrhosis and hepatocellular carcinoma. The activation of transforming growth factor-β (TGF-β) signaling is considered a critical event during EMT, and efforts have been made to screen small molecules that interfere with the TGF-β signaling pathway during EMT. Recently, a team of researchers, led by Prof. DING Xiaoyan at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, demonstrated that sorafenib improves liver fibrosis by the inhibition of TGF-β1-mediated EMT and apoptosis in mouse hepatocytes.

 

Given the prominent role of TGF-β in EMT and fibrogenesis, a number of strategies for blocking TGF-β signaling have been proposed. Small molecules targeting this signaling cascade have great therapeutic potential. To identify such candidates, Dr. CHEN Yue-Lei and his colleagues, under the supervision of Prof. DING Xiaoyan, performed a drug library screen using a luciferase reporter that is activated in response to a wide range of TGF-β1 concentrations. They identified sorafenib, a clinical agent that inhibits TGF-β signaling. When applied to AML12 cells and primary hepatocytes, sorafenib strikingly suppressed TGF-β1-induced EMT and apoptosis. Additionally, sorafenib inhibited TGF-β1-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). They further presented in vitro and in vivo evidence that sorafenib ameliorates the pro-apoptotic and pro-fibrotic effects of TGF-β in mouse primary hepatocytes, suggesting that this drug exerts a protective effect on hepatocytes and has therapeutic potential for the treatment of liver fibrosis.

 

This work entitled “Sorafenib Inhibits Transforming Growth Factor β1-Mediated Epithelial-Mesenchymal Transition and Apoptosis in Mouse Hepatocytes” was published in Hepatology on Apr. 22th, 2011.

 

This work was collaborated with Prof. LIU Ping (Shuguang Hospital, Shanghai University of Traditional Chinese Medicine), and supported by grants from the National Basic Research Program of China, the National Natural Science Foundation of China and the Knowledge Innovation Program of Shanghai Institutes for Biological Sciences. (SIBCB)

 

AUTHOR CONTACT:

Prof. DING Xiaoyan

Address: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, P. R. China

Tel: +86-21-54921411; E-mail: xyding@sunm.shcnc.ac.cn