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.

最近发现 Smad7（抗十肢麻痹同源物 7 之母）基因的多态性与结直肠癌发生风险增加有关。 Smad7 是 TGF-β（转化生长因子 β）信号通路的关键调节因子，通过调节增殖、细胞死亡和上皮细胞可塑性，在肿瘤发生的各个阶段发挥着重要作用。然而，最近的研究表明，Smad7 还影响其他中央通路（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 发挥作用。事实上，我们自己的初步数据表明，Smad7 虽然对于稳定状态下的胚胎肠道发育或组织稳态不是必需的，但在结肠癌的发展中至关重要，因为与对照组相比，肠上皮中缺乏 Smad7 的小鼠产生的肿瘤明显减少。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 缺陷和丰富的小鼠。此外，我们将研究 SMAD7 在肠上皮细胞中 TGF-β 依赖性和非依赖性信号通路中的参与。最后，我们将研究扩展到癌症相关的成纤维细胞 SMAD7 及其在成纤维细胞-上皮通讯中的参与。