Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations.
Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations.
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发表时间：
2004
期刊：
影响因子：
11.2
通讯作者：
N. Harada;H. Oshima;M. Katoh;Y. Tamai;M. Oshima;M. Taketo
中科院分区：
文献类型：
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作者：
N. Harada;H. Oshima;M. Katoh;Y. Tamai;M. Oshima;M. Taketo
我们之前已经建立了一种小鼠品系，其含有突变的β-连环蛋白等位基因，其外显子3被loxP序列夹在中间[Catnb（lox（ex 3））]。在这种小鼠品系中，单独的Wnt激活β-连环蛋白突变不足以引起肝癌，但可能需要额外的突变或表观遗传变化。在这里，我们报告，肝细胞癌的发展在100%的发病率在β-连环蛋白和H-ras基因的同时突变，由腺病毒介导的Cre表达引入的小鼠。虽然H-ras突变单独迅速引起肝细胞中的大细胞发育不良，但这些细胞在感染Cre-腺病毒后1周内没有显示自主生长。然而，在β-连环蛋白基因中的额外突变的同时诱导引起这种发育不良细胞的克隆扩增，随后结节形成和肝细胞癌的发展。这些结果表明，β-连环蛋白突变在肝癌发生中起着关键作用，与另一种癌基因的合作，这些小鼠提供了一个方便的模型，研究肝癌发生的早期步骤。
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.