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-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. Copyright 2005 S. Karger AG, Basel.
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-betaRI/RII) were analyzed in clinical HCCs and the humanhepatoma 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 humanplasminogen 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. Copyright 2005 S. Karger AG, Basel.
Authors: Ken Maes; Elizabeta Nemeth; G David Roodman; Alissa Huston; Flavia Esteve; Cesar Freytes; Natalie Callander; Eirini Katodritou; Lisa Tussing-Humphreys; Seth Rivera; Karin Vanderkerken; Alan Lichtenstein; Tomas Ganz Journal: Blood Date: 2010-08-02 Impact factor: 22.113
Authors: Sobia Zaidi; Richard Amdur; Xiyan Xiang; Herbert Yu; Linda L Wong; Shuyun Rao; Aiwu R He; Karan Amin; Daewa Zaheer; Raj K Narayan; Sanjaya K Satapathy; Patricia S Latham; Kirti Shetty; Chandan Guha; Nancy R Gough; Lopa Mishra Journal: Genes Cancer Date: 2022-06-06
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