Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations.
We have established previously a mouse strain containing a mutant beta-catenin allele of which exon 3 was sandwiched by loxP sequences [Catnb(lox(ex3))]. In this mouse strain, a Wnt-activating beta-catenin mutation alone is insufficient for hepatocarcinogenesis, but additional mutations or epigenetic changes may be required. Here we report that hepatocellular carcinoma develops at the 100% incidence in mice with simultaneous mutations in the beta-catenin and H-ras genes that are introduced by adenovirus-mediated Cre expression. Although H-ras mutation alone rapidly causes large cell dysplasia in the hepatocytes, these cells show no autonomous growth within 1 week after infection of the Cre-adenovirus. However, simultaneous induction of an additional mutation in the beta-catenin gene causes a clonal expansion of such dysplastic cells, followed by nodular formation and development of hepatocellular carcinoma. These results indicate that beta-catenin mutations play a critical role in hepatocarcinogenesis in cooperation with another oncogene and that these mice provide a convenient model to investigate early steps of hepatocarcinogenesis.
Harada
Naomoto
N
Banyu Tsukuba Research Institute (Merck), Tsukuba, Japan.
Oshima
Hiroko
H
Katoh
Masahiro
M
Tamai
Yositaka
Y
Oshima
Masanobu
M
Taketo
Makoto M
MM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005091:Exons; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin