title: Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice.
abstract: Hepatocellular carcinoma (HCC) represents the fifth-most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep-/-mice display sex-specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28-dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male-restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28hep-/--associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high-fat diet challenge.
  
  
  
  This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer-prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017;66:235-251).
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Cassano
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Piersigilli
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Suk Min
authors.initials: SM
authors.lastname: Jang
authors.affiliation: Clinical Chemistry Laboratory, Lausanne University Hospital, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Henry
authors.affiliation: Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Markus B
authors.initials: MB
authors.lastname: Geuking
authors.affiliation: Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mooser
authors.affiliation: Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Mucosal Immunology Lab, Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Macpherson
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D057890:Epigenomics / Q000379:methods; D005260:Female; D042822:Genomic Instability; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010641:Phenotype; D011897:Random Allocation; D012097:Repressor Proteins / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28