Altered expression of TGF-β receptors in hepatocellular carcinoma -: Effects of a constitutively active TGF-β type I receptor mutant

Background/Aims: Hepatocellular carcinomas (HCC) often show resistance to the effects of transforming growth factor-beta (TGF-beta). This study focuses on molecular mechanisms of this resistance to explore ways to overcome it. Methods: Transcription and protein expression of TGF-beta type I and type II receptors (TGF-beta RI/RII) were analyzed in clinical HCCs and the human hepatoma cell lines HuH-7 and HepG2. HuH-7 cells were transiently and stably transfected with a constitutively active TGF-beta RI mutant (CA TGF-beta RI). Resulting growth kinetics, integrin expression, invasiveness, TGF-beta-mediated activation of human plasminogen activator inhibitor type-1 (PAI-1) promoter and Smad expression were determined. Results: In clinical HCCs, there was less TGF-beta RII (6/10 cases) and more TGF-beta RI (8/10 cases) protein expression detectable in tumor compared to adjacent liver tissue. In HuH-7 cells, TGF-beta RII expression was likewise decreased. Cells transiently transfected with CA TGF-beta RI exhibited strong TGF-beta-related PAI-1 promoter activation. Stably transfected cells showed an attenuated response of the PAI-1 promoter, but increased Smad7 expression. Proliferation of stable clones was decreased. There was no change in integrin expression or invasiveness. Conclusions: Decreased TGF-beta RII protein expression might cause TGF-beta resistance in a subset of clinical HCCs. Stable transfection with CA TGF-beta RI reverses this in HuH-7 cells without increasing invasiveness. Copyright (C) 2005 S. Karger AG, Basel.