Cross-talk between TGFβ1 and EGFR signalling pathways induces TM4SF5 expression and epithelial-mesenchymal transition.
2012
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
mesenchymalcell features, using human and mouse normal hepatocytes. We found that TGFβ1 (transforming growth factor β1)-mediated
Smadactivation 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
Smadsto EGFR for TM4SF5 expression. Further, TGFβ1-mediated EGFR activation and TM4SF5 expression were abolished by EGFR suppression or extracellular EGF depletion.
Smadoverexpression mediated EGFR activation and TM4SF5 expression in the absence of serum, and EGFR kinase inactivation or EGF depletion abolished
Smad-overexpression-induced TM4SF5 and
mesenchymalcell 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
mesenchymalcell features, suggesting that TM4SF5 induction may be involved in the development of liver pathologies.
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