α-Catenin is essential in intestinal adenoma formation
α-Catenin is essential in intestinal adenoma formation
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DOI：
10.1073/pnas.0705730104
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发表时间：
2007-11
期刊：
影响因子：
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通讯作者：
H. Shibata;H. Takano;Masaki Ito;H. Shioya;M. Hirota;H. Matsumoto;Y. Kakudo;C. Ishioka;T. Akiyama;Y. Kanegae;I. Saito;T. Noda
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文献类型：
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作者：
H. Shibata;H. Takano;Masaki Ito;H. Shioya;M. Hirota;H. Matsumoto;Y. Kakudo;C. Ishioka;T. Akiyama;Y. Kanegae;I. Saito;T. Noda
APC基因功能缺失突变启动结直肠癌发生虽然肿瘤起始的分子机制是复杂的，但已经使用小鼠模型（包括ApcMin小鼠）鉴定了几种修饰基因。在家族性腺瘤性息肉病小鼠品系中，在Apc的密码子580处携带截短突变（Apc 580 D），一个品系（品系19-Apc 580 D/+）显示肠腺瘤的发生率显著降低（与其他品系相比<5%）。广泛的遗传分析确定了α-连环蛋白（Ctnna 1）基因的缺失是这种抑制的原因。值得注意的是，只有当Ctnna 1缺失与Apc 580 D突变处于顺式构型时才发生抑制。在19-Apc 580 D/+系产生的所有腺瘤中，Apc和Ctnna 1基因座之间的体细胞重组保留了野生型Ctnna 1等位基因。这些数据有力地表明，在肿瘤发生过程中，α-连环蛋白和Apc的同时失活抑制了19-Apc 580 D/+细胞系中的腺瘤形成，表明α-连环蛋白在肠腺瘤的发生中起着重要作用。尽管从具有侵袭性或转移性潜能的人类结肠肿瘤中获得的越来越多的证据已经确立了α-连环蛋白在晚期肿瘤发生中的肿瘤抑制作用，但是α-连环蛋白在肠肿瘤发生的起始中的作用没有得到很好的记录，特别是与β-连环蛋白相比。本研究中使用的小鼠模型集中在肿瘤起始的早期阶段，并清楚地表明α-连环蛋白的重要作用。因此，α-连环蛋白在肠道肿瘤发生中具有双重作用，在肿瘤起始中起支持作用，在肿瘤进展中起抑制作用。
A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line19-Apc580D/+) showed a remarkably reduced incidence of intestinal adenomas (<5% compared with other lines). Extensive genetic analysis identified a deletion in the α-catenin (Ctnna1) gene as the cause of this suppression. Notably, the suppression only occurred when the Ctnna1 deletion was in cis-configuration with the Apc580D mutation. In all adenomas generated in line19-Apc580D/+, somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of α-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc580D/+, suggesting that α-catenin plays an essential role in the initiation of intestinal adenomas. Although accumulating evidence obtained from human colon tumors with invasive or metastatic potential has established a tumor-suppressive role for α-catenin in late-stage tumorigenesis, the role of α-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of β-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for α-catenin. Thus, α-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.