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

Smad7 对肠上皮稳态和结直肠癌发展的功能作用

• 批准号: 319451951
• 负责人: Professor Dr. Christoph Becker
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319451951?language=en
• 关键词: Functional; role; Smad7; intestinal; epithelial

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.

Smad 7（母亲对decapentaplegic同系物-7）基因的多态性最近与结直肠癌的发展风险增加有关。Smad 7是TGF-β（转化生长因子β）信号通路的关键调节因子，其通过调节增殖、细胞死亡和上皮细胞可塑性在肿瘤发生的所有阶段中起重要作用。然而，最近的研究表明，Smad 7也影响其他中枢通路（即NF-κ B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TGF-β发挥作用。事实上，我们自己的初步数据表明，Smad 7虽然不是胚胎肠道发育或稳态组织稳态所必需的，但在结肠癌的发展中起着关键作用，因为与对照组相比，肠上皮中Smad 7缺陷的小鼠发展出的肿瘤明显较少。为了更好地了解Smad 7在肠道肿瘤发展的不同阶段中的作用，我们的目的是分析在已建立的结直肠癌小鼠模型中缺乏和精通Smad 7的小鼠。此外，我们将研究SMAD 7在肠上皮中的TGF-β依赖性和非依赖性信号通路中的参与。最后，我们将把我们的研究扩展到癌症相关的成纤维细胞SMAD 7及其参与成纤维细胞-上皮细胞通讯。