title: Antagonistic regulation of transmembrane 4 L6 family member 5 attenuates fibrotic phenotypes in CCl(4) -treated mice.
abstract: 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 in vitro and a CCl(4) -mediated mouse liver in vivo model, we examined whether TM4SF5 is expressed during liver fibrosis mediated by CCl(4) 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 in vitro. In the CCl(4) -mediated mouse liver model, TM4SF5 was expressed during the liver fibrosis mediated by CCl(4) 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.
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Cell Dynamics Research Center, College of Pharmacy, Seoul National University, Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Sook Young
authors.initials: SY
authors.lastname: Park
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D024042:Collagen Type I / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C540441:4'-(4-toluenesulfonylamido)-4-hydroxychalcone; D000199:Actins; D024042:Collagen Type I; D008565:Membrane Proteins; D013449:Sulfonamides; C111029:TM4SF5 protein, human; C570858:TM4SF5 protein, mouse; D053773:Transforming Growth Factor beta1; D002599:Chalcone; D004815:Epidermal Growth Factor; D002251:Carbon Tetrachloride