title: HBx triggers either cellular senescence or cell proliferation depending on cellular phenotype.
abstract: Replicative senescence is a hallmark of chronic liver diseases including chronic hepatitis B virus (HBV) infection, whereas HBV-encoded oncoproteins HBx and preS2 have been found to overcome senescence. HBx possesses a C-terminal truncation mainly in hepatocellular carcinomas but also in noncancerous liver tissues. Here, by cell counting, BrdU incorporation, MTT proliferation assay, cell cycle analysis, SA-βgal staining and Western blotting in primary and malignant cells, we investigated the effect of HBx C-terminal mutants on cellular senescence. HBx C-terminal mutants were found to trigger cellular senescence in primary MRC5 cells, and malignant liver cells Huh7, and SK-Hep1. In contrast, these mutants promoted the proliferation of HepG2 malignant liver cells. The pro-senescent effect of HBx relied on an increased p16(INK4a) and p21(Waf1/Cip1) expression, and a decreased phosphorylation of Rb. Together, these results suggest that the two main variants of HBx present in HBV-infected liver possess opposite effects on cellular senescence that depend on the phenotype of infected cells.
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.
authors: M E
authors: ME
authors: Idrissi
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.
authors: H
authors: H
authors: Hachem
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.
authors: C
authors: C
authors: Koering
authors: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.|Université Lyon-1, Villeurbanne, France.|Hospices Civils de Lyon, Service d'Hépatologie et de Gastroentérologie, Groupement Hospitalier Lyon Nord, Lyon, France.
authors: P
authors: P
authors: Merle
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.
authors: M
authors: M
authors: Thénoz
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.
authors: F
authors: F
authors: Mortreux
authors: Université Lyon-1, CNRS UMR5239, Oncovirologie et Biothérapies, Lyon, France.|Université Lyon-1, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
authors: E
authors: E
authors: Wattel
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D056945:Hep G2 Cells; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000473:pathology / Q000821:virology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C050807:presurface protein 2, hepatitis B surface antigen; D001616:beta-Galactosidase
keywords: HBx; cell cycle; cellular senescence; hepatitis B virus-encoded oncoproteins; malignant liver cells; preS2