Harada Naomoto, Oshima Hiroko, Katoh Masahiro, Tamai Yositaka, Oshima Masanobu, Taketo Makoto M
Banyu Tsukuba Research Institute (Merck), Tsukuba, Japan.
Cancer Res. 2004 Jan 1;64(1):48-54. doi: 10.1158/0008-5472.can-03-2123.
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.
我们先前已建立了一种小鼠品系，其含有一个突变的β-连环蛋白等位基因，该等位基因的外显子3被loxP序列夹在中间[Catnb(lox(ex3))]。在这种小鼠品系中，仅Wnt激活的β-连环蛋白突变不足以引发肝癌发生，但可能还需要额外的突变或表观遗传变化。在此我们报告，通过腺病毒介导的Cre表达引入β-连环蛋白和H-ras基因同时突变的小鼠中，肝癌的发生率为100%。尽管单独的H-ras突变会迅速导致肝细胞出现大细胞发育异常，但在感染Cre-腺病毒后1周内，这些细胞并未表现出自主生长。然而，β-连环蛋白基因中额外突变的同时诱导会导致此类发育异常细胞的克隆性扩增，随后形成结节并发展为肝癌。这些结果表明，β-连环蛋白突变与另一个癌基因协同作用在肝癌发生中起关键作用，并且这些小鼠为研究肝癌发生的早期步骤提供了一个便利的模型。
