Xu X, Brodie S G, Yang X, Im Y H, Parks W T, Chen L, Zhou Y X, Weinstein M, Kim S J, Deng C X
Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
Oncogene. 2000 Apr 6;19(15):1868-74. doi: 10.1038/sj.onc.1203504.
The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-beta signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6 - 12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-beta1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.
肿瘤抑制因子SMAD4，也称为DPC4，在胰腺癌中缺失，是转化生长因子-β（TGF-β）信号传导的核心介质。先前的研究表明，Smad4基因纯合无效突变（Smad4-/-）的小鼠在原肠胚形成之前死亡，表现出胚外膜形成受损和内胚层分化异常。在此我们表明，Smad4+/-小鼠在6至12个月大时开始在胃底和胃窦出现息肉病，在老年动物的十二指肠和盲肠出现息肉的频率较低。随着年龄的增长，胃窦息肉呈现出从增生到发育异常、原位癌，最终发展为浸润癌的一系列变化。这些改变始于胃上皮细胞中Smad4表达部位的显著扩张。然而，仅在肿瘤进展的后期才检测到剩余Smad4野生型等位基因的缺失，这表明Smad4单倍体不足足以引发肿瘤。我们的数据还表明，TGF-β1和细胞周期蛋白D1的过表达与胃息肉和肿瘤的增殖增加有关。这些研究表明，Smad4在胃肠道中起肿瘤抑制作用，也为筛选促进或预防胃肿瘤发生的因素提供了有价值的模型。
