Functional role of Smad7 on intestinal epithelial homeostasis and colorectal cancer development

Smad7基因多态性（母体抗十碳五苯瘫同源基因-7）最近被发现与结直肠癌发病风险增加有关。Smad7是tgf - β（转化生长因子β）信号通路的关键调控因子，tgf - β通过调控增殖、细胞死亡和上皮细胞可塑性在肿瘤发生的各个阶段发挥重要作用。然而，最近的研究表明，Smad7也影响其他中枢通路（即NF-kappaB和β -catenin）和参与肿瘤发展的细胞过程，并且可以独立于tgf - β起作用。事实上，我们自己的初步数据表明，Smad7虽然不是胚胎肠道发育或稳定状态下组织稳态所必需的，但在结肠癌的发展中却至关重要，因为肠上皮中缺乏Smad7的小鼠与对照组相比，患肿瘤的几率要低得多。为了更好地了解Smad7在肠道肿瘤发展的不同阶段中的作用，我们旨在分析Smad7缺失和精通的小鼠在已建立的结直肠癌小鼠模型中的表达。此外，我们将研究SMAD7在肠上皮中tgf - β依赖性和非依赖性信号通路中的作用。最后，我们将把我们的研究扩展到癌症相关的成纤维细胞SMAD7及其参与成纤维细胞-上皮细胞通讯。

Polymorphisms in the Smad7 (mother against decapenthaplegic homolog-7) gene have recently been associated with an increased risk for the development of colorectal cancer. Smad7 is a key regulator of the TGF-beta (transforming growth factor beta) signaling pathway which plays an important role during all stages of tumor genesis via regulation of proliferation, cell death and epithelial cell plasticity. However, recent studies suggest that Smad7 also influences other central pathways (i.e. NF-kappaB and beta-catenin) and cellular processes involved in tumor development and can act independently from TGF-beta. Indeed, our own preliminary data demonstrate that Smad7 though not essential for embryonic gut development or tissue homeostasis in the steady state, is critically involved in colon cancer development, as mice deficient for Smad7 in the intestinal epithelium developed significantly less tumors as compared to controls. In order to better understand the role of Smad7 during different stages of tumor development in the gut, we aim to analyse mice deficient and proficient for Smad7 in established mouse models of colorectal cancer. Moreover, we will investigate the involvement of SMAD7 in TGF-beta-dependent and -independent signalling pathways in the intestinal epithelium. Finally we will extend our studies to cancer associated fibroblast SMAD7 and its involvement in fibroblast-epithelial communication.