title: Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial-mesenchymal transition.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.forename: Suyong
authors.initials: S
authors.lastname: Choi
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Sin-Ae
authors.initials: SA
authors.lastname: Lee
authors.forename: Tae Kyoung
authors.initials: TK
authors.lastname: Kwak
authors.forename: Hyeonjung
authors.initials: H
authors.lastname: Kim
authors.forename: Oisun
authors.initials: O
authors.lastname: Jung
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.forename: Youra
authors.initials: Y
authors.lastname: Ko
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.forename: Yoon-Ju
authors.initials: YJ
authors.lastname: Choi
authors.forename: Doyoung
authors.initials: D
authors.lastname: Jeong
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Lee
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: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C111029:TM4SF5 protein, human; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors