Infection of HepG2 cells with recombinant adenovirus encoding the HCV core protein induces p21(WAF1) down-regulation -- effect of transforming growth factor beta.
OBJECTIVE
Chronic infection with hepatitis C virus leads to liver cirrhosis and hepatocellular carcinoma. Hepatocellular carcinoma is sometimes associated with p53 dysfunction and decreased p21(WAF1) expression. The p21(WAF1) gene is a major target of p53, and p21(WAF1) protein regulates the activities of cyclin/CDK complexes involved in cell cycle control and tumor formation. Because core protein has oncogenic properties, we investigated the expression of p21(WAF1) following core expression.


METHODS
We analyzed by Western blot, Northern blot and transfection the expression of p21(WAF1) in HepG2 cell line under transient expression of Hepatitis C core protein by recombinant-adenoviral infection.


CONCLUSIONS
Infection of HepG2 with core-encoding viruses induced the down-regulation of p21(WAF1) expression. This effect is due to a decrease in the p21(WAF1) gene transcription and of the p21(WAF1) protein half-life. These results support a role for Hepatitis C virus core protein in cell transformation. We also found also that the transforming growth factor beta can counteract the core-induced p21(WAF1) down-regulation. The antagonist effect of TGF beta, or of other molecules, on p21(WAF1) expression may be of particular interest for the treatment of HCV-positive hepatocellular carcinoma.
Dubourdeau
Marc
M
Macrophages, Médiateurs de l'Inflammation et Interactions Cellulaires UPRES EA 2405-INSERM IFR 31, CHU Rangueil, Bât L1, 1 avenue Jean Poulhes, 31403 Toulouse cedex 04, France.
Miyamura
Tatsuo
T
Matsuura
Yoshiharu
Y
Alric
Laurent
L
Pipy
Bernard
B
Rousseau
Denis
D
D000256:Adenoviridae / Q000235:genetics; D006528:Carcinoma, Hepatocellular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms; D011994:Recombinant Proteins / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014758:Viral Core Proteins / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D001616:beta-Galactosidase