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Liver-targeted disruption of Apc in mice activates βcatenin signaling and leads to hepatocellular carcinomas.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 12/7/2004, Vol. 101 Issue 49, p17216-17221, 6p
- Publication Year :
- 2004
-
Abstract
- Although inappropriate activation of the Wnt/β-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<superscript>lox/lox</superscript>, 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<superscript>9</superscript> plaque-forming units (pfu) per mouse) inactivated the Apc gene in the liver and resulted in marked hepatomegaly, hepatocyte hyperplasia, and rapid mortality. β-Catenin signaling activation was demonstrated by nuclear and cytoplasmic accumulation of β-catenin in the hepatocytes and by the induction of β-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 × 10<superscript>9</superscript> pfu per mouse), compatible with both survival and persistence of β-catenin-activated cells. In these conditions, 67% of mice developed HCC. β-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/β-catenin pathway by invalidation of Apc is required for liver tumorigenesis. [ABSTRACT FROM AUTHOR]
- Subjects :
- BILIARY tract
ABDOMEN
LIVER cancer
CARCINOGENESIS
LIVER cells
AMINO acids
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 101
- Issue :
- 49
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 15513323
- Full Text :
- https://doi.org/10.1073/pnas.0404761101