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

Smad7(母亲抗十头瘫同源基因-7)基因的多态最近被认为与结直肠癌发生的风险增加有关。Smad7是转化生长因子β信号通路的关键调节因子，通过调节细胞增殖、细胞死亡和上皮细胞的可塑性，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(即核因子-kappaB和β-连环蛋白)和参与肿瘤发展的细胞过程，并且可以独立于转化生长因子-β发挥作用。事实上，我们自己的初步数据表明，尽管Smad7对胚胎肠道发育或稳定状态下的组织动态平衡不是必不可少的，但它与结肠癌的发展密切相关，因为肠道上皮中Smad7基因缺陷的小鼠与对照组相比发生的肿瘤明显较少。为了更好地了解Smad7在肠道肿瘤发展的不同阶段中的作用，我们的目标是在已建立的结直肠癌小鼠模型中分析Smad7缺乏和熟练的小鼠。此外，我们还将研究Smad7在肠上皮中转化生长因子-β依赖和非依赖的信号通路中的作用。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及其在成纤维细胞-上皮细胞通讯中的作用。

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.