Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas.
Although inappropriate activation of the Wnt/beta-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, Apc(lox/lox), in which exon 14 of the tumor-suppressor gene adenomatous polyposis coli (Apc) is flanked by loxP sequences. i.v. injection of adenovirus encoding Cre recombinase (AdCre) at high multiplicity [10(9) plaque-forming units (pfu) per mouse] inactivated the Apc gene in the liver and resulted in marked hepatomegaly, hepatocyte hyperplasia, and rapid mortality. beta-Catenin signaling activation was demonstrated by nuclear and cytoplasmic accumulation of beta-catenin in the hepatocytes and by the induction of beta-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 x 10(9) pfu per mouse), compatible with both survival and persistence of beta-catenin-activated cells. In these conditions, 67% of mice developed HCC. beta-Catenin signaling was strongly activated in these Apc-inactivated HCCs. The HCCs were well, moderately, or poorly differentiated. Indeed, their histological and molecular features mimicked human HCC. Thus, deletion of Apc in the liver provides a valuable model of human HCC, and, in this model, activation of the Wnt/beta-catenin pathway by invalidation of Apc is required for liver tumorigenesis.
Colnot
S
S
Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris V, 24 Rue du Faubourg St. Jacques, 75014 Paris, France.
Decaens
T
T
Niwa-Kawakita
M
M
Godard
C
C
Hamard
G
G
Kahn
A
A
Giovannini
M
M
Perret
C
C
D000818:Animals; D003598:Cytoskeletal Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017491:Genes, APC; D005822:Genetic Vectors / Q000008:administration & dosage; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D015398:Signal Transduction; D015996:Survival Rate; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin