Smad4 haploinsufficiency in mouse models for intestinal cancer
Smad4 haploinsufficiency in mouse models for intestinal cancer
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DOI：
10.1038/sj.onc.1209226
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发表时间：
2006-03-23
期刊：
影响因子：
8
通讯作者：
Fodde, R
中科院分区：
文献类型：
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作者：
Alberici, P;Jagmohan-Changur, S;Fodde, R
Smad4(+/E6ad)小鼠携带内源性Smad4基因零突变，导致上胃肠道锯齿状腺瘤和混合性息肉病，外显率为100%。在这里，我们通过杂合性缺失(LOH)分析和免疫组织化学(IHC)显示，虽然大多数肿瘤出现在9个月龄时，但野生型Smad4等位基因的体细胞丢失仅发生在肿瘤进展的后期阶段。因此，单倍体功能不全是Smad4驱动的胃肠道肿瘤启动的基础。由于APC和Smad4抑癌基因都定位在小鼠的18号染色体上，我们用APC(+/1638N)模型培育了Smad4(+/E6sad)，以产生两个不同的复合杂合系，它们既有顺式突变(CAS)，也有反式突变(TAS)。值得注意的是，两种模型都显示出与单个突变后代相比，肿瘤的多样性增加，尽管CAS小鼠受到的影响更严重，在5-6周大时就死亡了。表型和分子分析表明，在APC功能丧失之前和之后，Smad4单倍体不足足以显著影响肿瘤的启动和进展。此外，Smad4的完全缺失极大地增强了APC驱动的肿瘤形成。
The Smad4(+/E6sad) mouse carries a null mutation in the endogenous Smad4 gene resulting in serrated adenomas and mixed polyposis of the upper gastrointestinal (GI) tract with 100% penetrance. Here, we show by loss of heterozygosity (LOH) analysis and immunohistochemistry (IHC) that, although the majority of the tumors appear at 9 months of age, somatic loss of the wild-type Smad4 allele occurs only at later stages of tumor progression. Hence, haploinsufficiency underlies Smad4-driven tumor initiation in the GI tract. As both the Apc and Smad4 tumor suppressor genes map to mouse chromosome 18, we have bred Smad4(+/E6sad) with the Apc(+/1638N) model to generate two distinct compound heterozygous lines carrying both mutations either in cis ( CAS) or in trans ( TAS). Strikingly, both models show increased tumor multiplicities when compared with the single mutant littermates, although CAS mice are more severely affected and became moribund at only 5-6 weeks of age. Phenotypic and molecular analyses indicate that Smad4 haploinsufficiency is sufficient to significantly affect tumor initiation and progression both prior to and upon loss of Apc function. Moreover, complete loss of Smad4 strongly enhances Apc-driven tumor formation.