Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers

• Kostas C Nikolaou ^[1] ; Panagiotis Moulos ^[1] ; George Chalepakis ^[2] ; Pantelis Hatzis ^[1] ; Hisanobu Oda ^[4] ; Danny Reinberg ^[3] ; Iannis Talianidis ^[1]
  1. [1] Alexander Fleming Biomedical Sciences Research Center

     Alexander Fleming Biomedical Sciences Research Center

     Dimos Athens, Grecia

     
  2. [2] University of Crete

     University of Crete

     Dimos Heraklion, Grecia

     
  3. [3] New York University

     New York University

     Estados Unidos

     
  4. [4] 3 Medical Institute of Bioregulation, Kyusyu University Fukuoka, Japan; 4 Gastrointestinal and Oncology Division, National Kyusyu Cancer Center Fukuoka, Japan

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 4, 2014, págs. 430-447
• Idioma: inglés
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  • PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to self-renew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes.