Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1866, Issue 4, Pages 588-597Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2019.01.001
Keywords
GP73; TGF-beta signaling; Caveolae-1; ERK; HCC
Categories
Funding
- National Natural Science Foundation of China [31471325, 31670761, 31571424, 31470850, 81671973, 81773205]
- Beijing Nova Program [Z171100001117121]
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Increased GP73 expression in hepatocytes from patients with acute hepatitis, through disease progression to cirrhosis and chronic liver disease suggests that progressive tissue remodeling and fibrogenesis are driving forces for GP73 upregulation. Nevertheless, details about regulation of GP73 expression and its biological functions remain elusive and await further characterization. In this study, we demonstrate that GP73 is a direct target of TGF-beta 1 transcriptional regulation. Its induced expression inhibits TGF-beta-Smad mediated growth suppression. On the other hand, elevated GP73 results in upregulation of ERK/Akt signaling induced by TGF-beta 1. Mechanistically, upregulation of lipid raft and caveolae-1 induced by GP73 overexpression mediates its regulatory effect on TGF-beta 1 signaling. Notably, lipid raft expression is elevated in HCC tumors and tissues with higher GP73 expression yield more intensive Flotillin staining. Our results establish the linkage between GP73 and TGF-beta signaling, indicating that GP73 may promote HCC tumorigenesis by selectively regulating TGF-beta signaling through lipid raft modulation.
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