Altered expression of TGF-beta receptors in hepatocellular carcinoma--effects of a constitutively active TGF-beta type I receptor mutant.
OBJECTIVE
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-betaRI/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-betaRI mutant (CA TGF-betaRI). 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-betaRII (6/10 cases) and more TGF-betaRI (8/10 cases) protein expression detectable in tumor compared to adjacent liver tissue. In HuH-7 cells, TGF-betaRII expression was likewise decreased. Cells transiently transfected with CA TGF-betaRI 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-betaRII protein expression might cause TGF-beta resistance in a subset of clinical HCCs. Stable transfection with CA TGF-betaRI reverses this in HuH-7 cells without increasing invasiveness.
Musch
Annemarie
A
Department of Medicine I, University of Bonn, Germany.
Rabe
Christian
C
Paik
Mignon-Denise
MD
Berna
Marc Jean
MJ
Schmitz
Volker
V
Hoffmann
Per
P
Nischalke
Hans Dieter
HD
Sauerbruch
Tilman
T
Caselmann
Wolfgang H
WH
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology*; D014407:Tumor Cells, Cultured
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta