{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:43:36Z","timestamp":1792460616530,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"49","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,12,7]]},"abstract":"<jats:p>\n                    Although inappropriate activation of the Wnt\/\u03b2-catenin pathway has been implicated in the development of hepatocellular carcinoma (HCC), the role of this signaling in liver carcinogenesis remains unclear. To investigate this issue, we constructed a mutant mouse strain,\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>lox\/lox<\/jats:sup>\n                    , in which exon 14 of the tumor-suppressor gene adenomatous polyposis coli (\n                    <jats:italic>Apc<\/jats:italic>\n                    ) is flanked by\n                    <jats:italic>loxP<\/jats:italic>\n                    sequences. i.v. injection of adenovirus encoding Cre recombinase (AdCre) at high multiplicity [10\n                    <jats:sup>9<\/jats:sup>\n                    plaque-forming units (pfu) per mouse] inactivated the\n                    <jats:italic>Apc<\/jats:italic>\n                    gene in the liver and resulted in marked hepatomegaly, hepatocyte hyperplasia, and rapid mortality. \u03b2-Catenin signaling activation was demonstrated by nuclear and cytoplasmic accumulation of \u03b2-catenin in the hepatocytes and by the induction of \u03b2-catenin target genes (glutamine synthetase, glutamate transporter 1, ornithine aminotransferase, and leukocyte cell-derived chemotaxin 2) in the liver. To test a long-term oncogenic effect, we inoculated mice with lower doses of AdCre (0.5 \u00d7 10\n                    <jats:sup>9<\/jats:sup>\n                    pfu per mouse), compatible with both survival and persistence of \u03b2-catenin-activated cells. In these conditions, 67% of mice developed HCC. \u03b2-Catenin signaling was strongly activated in these\n                    <jats:italic>Apc<\/jats:italic>\n                    -inactivated HCCs. The HCCs were well, moderately, or poorly differentiated. Indeed, their histological and molecular features mimicked human HCC. Thus, deletion of\n                    <jats:italic>Apc<\/jats:italic>\n                    in the liver provides a valuable model of human HCC, and, in this model, activation of the Wnt\/\u03b2-catenin pathway by invalidation of\n                    <jats:italic>Apc<\/jats:italic>\n                    is required for liver tumorigenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0404761101","type":"journal-article","created":{"date-parts":[[2004,11,24]],"date-time":"2004-11-24T20:24:43Z","timestamp":1101327883000},"page":"17216-17221","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":319,"title":["Liver-targeted disruption of\n                    <i>Apc<\/i>\n                    in mice activates \u03b2-catenin signaling and leads to hepatocellular carcinomas"],"prefix":"10.1073","volume":"101","author":[{"given":"S.","family":"Colnot","sequence":"first","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Decaens","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Niwa-Kawakita","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Godard","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Hamard","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Kahn","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; and Centre d'\u00c9tude du Polymorphisme Humain, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U434, 27 Rue Juliette Dodu, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Giovannini","sequence":"additional","affiliation":[{"name":"Institut Cochin, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U567, Centre National de la Recherche Scientifique, Unit\u00e9 Mixte de Recherche 8104, Universit\u00e9 Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France; 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