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Kang, Minkyung,Choi, Suyong,Jeong, Soo-Jin,Lee, Sin-Ae,Kwak, Tae Kyoung,Kim, Hyeonjung,Jung, Oisun,Lee, Mi-Sook,Ko, Youra,Ryu, Jihye,Choi, Yoon-Ju,Jeong, Doyoung,Lee, Hyo Jeong,Ye, Sang-Kyu,Kim, Sung- Biochemical Society 2012 The Biochemical journal Vol.443 No.3
<P>The EMT (epithelial-mesenchymal transition) is involved in fibrosis and cancer, and is regulated by different signalling pathways mediated through soluble factors, actin reorganization and transcription factor actions. Because the tetraspan (also called tetraspanin) TM4SF5 (transmembrane 4 L6 family member 5) is highly expressed in hepatocellular carcinoma and induces EMT, understanding how TM4SF5 expression in hepatocytes is regulated is important. We explored the mechanisms that induce TM4SF5 expression and whether impaired signalling pathways for TM4SF5 expression inhibit the acquisition of mesenchymal cell features, using human and mouse normal hepatocytes. We found that TGFβ1 (transforming growth factor β1)-mediated Smad activation caused TM4SF5 expression and EMT, and activation of the EGFR [EGF (epidermal growth factor) receptor] pathway. Inhibition of EGFR activity following TGFβ1 treatment abolished acquisition of EMT, suggesting a link from Smads to EGFR for TM4SF5 expression. Further, TGFβ1-mediated EGFR activation and TM4SF5 expression were abolished by EGFR suppression or extracellular EGF depletion. Smad overexpression mediated EGFR activation and TM4SF5 expression in the absence of serum, and EGFR kinase inactivation or EGF depletion abolished Smad-overexpression-induced TM4SF5 and mesenchymal cell marker expression. Inhibition of Smad, EGFR or TM4SF5 using Smad7 or small compounds also blocked TM4SF5 expression and/or EMT. These results indicate that TGFβ1- and growth factor-mediated signalling activities mediate TM4SF5 expression leading to acquisition of mesenchymal cell features, suggesting that TM4SF5 induction may be involved in the development of liver pathologies.</P>
Kang, Minkyung,Jeong, Soo‐,Jin,Park, Sook Young,Lee, Hyo Jeong,Kim, Hyun Jeong,Park, Ki Hun,Ye, Sang‐,Kyu,Kim, Sung‐,Hoon,Lee, Jung Weon Blackwell Publishing Ltd 2012 FEBS JOURNAL Vol.279 No.4
<P>The development of liver fibrosis from chronic inflammation can involve epithelial–mesenchymal transition (EMT). Severe liver fibrosis can progress to cirrhosis, and further to hepatocellular carcinoma. Because the tetraspanin transmembrane 4 L6 family member 5 (TM4SF5) induces EMT and is highly expressed in hepatocellular carcinoma, it is of interest to investigate whether TM4SF5 expression is correlated with EMT processes during the development of fibrotic liver features. Using hepatic cells <I>in vitro</I> and a CCl<SUB>4</SUB>‐mediated mouse liver <I>in vivo</I> model, we examined whether TM4SF5 is expressed during liver fibrosis mediated by CCl<SUB>4</SUB> administration and whether treatment with anti‐TM4SF5 reagent blocks the fibrotic liver features. Here, we found that TM4SF5 expression was induced by the transforming growth factor (TGF)β1 and epidermal growth factor signaling pathways in hepatocytes <I>in vitro</I>. In the CCl<SUB>4</SUB>‐mediated mouse liver model, TM4SF5 was expressed during the liver fibrosis mediated by CCl<SUB>4</SUB> administration and correlated with α‐smooth muscle actin expression, collagen I deposition, and TGFβ1 and epidermal growth factor receptor signaling activation in fibrotic septa regions. Interestingly, treatment with anti‐TM4SF5 reagent blocked the TM4SF5‐mediated liver fibrotic features: the formation of fibrotic septa with α‐smooth muscle actin expression and collagen I deposition was attenuated by treatment with anti‐TM4SF5 reagent. These results suggest that TM4SF5 expression mediated by TGFβ1 and growth factor can facilitate fibrotic processes during chronic liver injuries. TM4SF5 is thus a candidate target for prevention of liver fibrosis following chronic liver injury.</P>