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Cross-talk between TGFβ1 and EGFR signaling pathways induces TM4SF5 expression and Epithelial-Mesenchymal Transition.
Cited 37 time in
Web of Science
Cited 41 time in Scopus
- Authors
- Issue Date
- 2012-05
- Publisher
- Portland Press
- Citation
- BIOCHEMICAL JOURNAL Vol.443 No.3, pp. 691-700
- Keywords
- 복합학
; epidermal growth factor receptor (EGFR)
; epithelial–
mesenchymal transition (EMT) ; gene induction ; signalling
cross-talk ; tetraspanin ; transforming growth factor β1 (TGFβ1)
- 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.
- ISSN
- 0264-6021
- Language
- English
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