Transcriptional repressors of E-cadherin in metastasis

转移中 E-钙粘蛋白的转录抑制因子

• 批准号: 6885592
• 负责人: KEVIN W FREEMAN
• 金额: $ 4.4万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885592
• 关键词: Transcriptional; repressors; cadherin; metastasis

DESCRIPTION (provided by applicant): Aggressive carcinomas are characterized by epithelial to mesenchymal transition (EMT). The hallmarks of EMT, loss of cell-cell interactions and an increase in cell motility, potentiate the exodus of cancer cells from the primary tumor site, increasing the likelihood of metastasis. In a number of epithelial cell lines continuous tumor growth factor beta 1 (TGF-beta1) signaling is necessary for initiating and maintaining EMT. Multiple TGF-beta1 induced transcriptional repressors (TITR) of E-cadherin have been implicated in EMT, including Snail, Slug, ZEB-1 and ZEB-2. We will test the hypothesis that a cell's commitment to EMT may be determined by positive and negative feedback loops involving the TITRs by using dominant negative versions of the TITRs, small interfering RNA (siRNA) directed towards the TITRs and overexpression of the individual TITRs in EpH4 cells. To firmly establish the role of these TITRs in EMT mediated metastasis, we will determine in vivo if the TITRs cause increased metastatic potential of EpH4 cells. Finally using a newly established genome wide screen based on siRNA we will identify shared downstream signaling factors of TGF-beta1 that control the expression of the TITRs, providing therapeutic targets for preventing metastasis.

描述（由申请人提供）：侵略性癌的特征是上皮过渡（EMT）。 EMT的标志，细胞 - 细胞相互作用的丧失和细胞运动的增加，增强了从原发性肿瘤部位的癌细胞外流，增加了转移的可能性。在许多上皮细胞系中，连续肿瘤生长因子1（TGF-BETA1）信号对于启动和维持EMT是必需的。 E-Cadherin的多种TGF-BETA1引起的转录阻遏物（TITR）与EMT有关，包括Snail，Slug，Zeb-1和Zeb-2。我们将检验以下假设：细胞对EMT的承诺可以由涉及TITR的正和负反馈回路来确定，该反馈通过使用TITR的显性负面版本，小型干扰RNA（SIRNA）针对EPH4细胞中单个TITRS的过表达。为了牢固确定这些TITR在EMT介导的转移中的作用，我们将在体内确定是否会导致EPH4细胞的转移潜力增加。最终，使用基于siRNA的新建立的基因组宽屏幕，我们将确定控制TITR表达的TGF-BETA1的共享下游信号传导因子，从而提供了预防转移的治疗靶标。