title: The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice.
abstract: Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Trierweiler
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hockenjos
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Zatloukal
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: H E
authors.initials: HE
authors.lastname: Blum
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre, Melchor Fernandez Almagro 3, E-28029 Madrid, Spain.
authors.forename: E F
authors.initials: EF
authors.lastname: Wagner
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Hasselblatt
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000235:genetics; D002472:Cell Transformation, Viral; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1