title: Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.
abstract: Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Rainer
authors.initials: R
authors.lastname: Hamacher
authors.affiliation: Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guío-Carrión
authors.affiliation: Spectroscopy and Nuclear Magnetic Resonance Spectroscopy Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Ramón
authors.identifier: 0000-0002-5743-2221
authors.initials: R
authors.lastname: Campos-Olivas
authors.affiliation: Flow Cytometry Core Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Lola
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Dienes
authors.affiliation: Department of Clinical Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Thomsen
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Hasenfuss
authors.affiliation: Genes, Development and Disease Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain ewagner@cnio.es.
authors.forename: Erwin F
authors.identifier: 0000-0001-7872-0196
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002784:Cholesterol / Q000502:physiology*; D004052:Diethylnitrosamine / Q000494:pharmacology; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology*; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins
chemical_list: D029721:Drosophila Proteins; D016760:Proto-Oncogene Proteins c-fos; D012097:Repressor Proteins; C075878:ttk protein, Drosophila; D004052:Diethylnitrosamine; D002784:Cholesterol