title: Protein phosphatase 2A promotes hepatocellular carcinogenesis in the diethylnitrosamine mouse model through inhibition of p53.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Most HCCs develop in cirrhotic livers. Alcoholic liver disease, chronic hepatitis B and chronic hepatitis C are the most common underlying liver diseases. Hepatitis C virus (HCV)-specific mechanisms that contribute to HCC are presently unknown. Transgenic expression of HCV proteins in the mouse liver induces an overexpression of the protein phosphatase 2A catalytic subunit (PP2Ac). We have previously reported that HCV-induced PP2Ac overexpression modulates histone methylation and acetylation and inhibits DNA damage repair. In this study, we analyze tumor formation and gene expression using HCV transgenic mice that overexpress PP2Ac and liver tissues from patients with HCC. We demonstrate that PP2Ac overexpression interferes with p53-induced apoptosis. Injection of the carcinogen, diethylnitrosamine, induced significantly more and larger liver tumors in HCV transgenic mice that overexpress PP2Ac compared with control mice. In human liver biopsies from patients with HCC, PP2Ac expression was significantly higher in HCC tissue compared with non-tumorous liver tissue from the same patients. Our findings demonstrate an important role of PP2Ac overexpression in liver carcinogenesis and provide insights into the molecular pathogenesis of HCV-induced HCC.
authors.affiliation: Department of Biomedicine and.
authors.forename: François H T
authors.initials: FH
authors.lastname: Duong
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Matter
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Makowska
authors.forename: Diego
authors.initials: D
authors.lastname: Calabrese
authors.forename: Tanja
authors.initials: T
authors.lastname: Dietsche
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ketterer
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
mesh_terms: D000818:Animals; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D005047:Etoposide / Q000031:analogs & derivatives / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D009943:Organophosphorus Compounds; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine; C061400:etoposide phosphate; D005047:Etoposide; D054648:Protein Phosphatase 2