Journal Article

Tumor formation in liver of conditional β-catenin-deficient mice exposed to a diethylnitrosamine/phenobarbital tumor promotion regimen

Benjamin Rignall, Albert Braeuning, Albrecht Buchmann and Michael Schwarz

in Carcinogenesis

Volume 32, issue 1, pages 52-57
Published in print January 2011 | ISSN: 0143-3334
Published online November 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq226
Tumor formation in liver of conditional β-catenin-deficient mice exposed to a diethylnitrosamine/phenobarbital tumor promotion regimen

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The antiepileptic drug phenobarbital (PB) is a potent tumor promoter in mouse liver, where it stimulates the selective outgrowth of tumor populations harboring activating mutations in Ctnnb1, encoding β-catenin. A tumor initiation–promotion study was conducted in mice with conditional hepatocyte-specific knockout (KO) of Ctnnb1 and in Ctnnb1 wild-type controls. Mice received a single injection of N-nitrosodiethylamine (DEN) at the age of 6 weeks followed by continuous administration of PB given in the diet (0.05%) for 27 weeks. Metabolic activation of DEN in hepatocytes from both Ctnnb1 wild-type and KO mice was demonstrated. PB strongly enhanced liver tumor formation in Ctnnb1 wild-type mice, and 90% of the PB-promoted tumors were Ctnnb1-mutated. A similar increase in carcinogenic response was seen when using glucose-6-phosphatase and glutamine synthetase as tumor markers. The prevalence of tumors in Ctnnb1 KO mice was ∼7-fold higher than in wild-type mice, suggesting an enhancing effect of the gene KO on liver tumor development. However, in strong contrast to wild-type mice, PB did not promote tumor formation in the Ctnnb1 KO mice. Livers of KO mice, particularly from the PB treatment group, demonstrated fibrosis and massive infiltration of immune cells, an effect not seen in wild-type mice. In summary, our data demonstrate that (i) liver tumor promotion by PB requires functional β-catenin signaling and (ii) absence of β-catenin enhances carcinogen-induced hepatocarcinogenesis and induces a pre-cirrhotic phenotype in mouse liver.

Journal Article.  4235 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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