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Molecular analyses of TGF-β-induced Epithelial-Mesenchymal Transition in oral cancer cells

TGF-β诱导口腔癌细胞上皮-间质转化的分子分析

基本信息

批准号：
18390496
负责人：
SAITOH Masao
金额：
$ 11.36万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390496/
关键词：
Epithelial-Mesenchymal Transtion EMT TGF-β Snail SIP1 ZEB1 シグナル伝達機構 Snai1 転写因子 E-cadherin

项目摘要

Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-β in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-β-induced EMT. In this study, we show that expression of δEF-1 family proteins, ZEB1 and SIP1, is gradually increased by TGF-β with expression profiles reciprocal to that of E-cadherin. SIP1 or ZEB1 dramatically downregulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing the expression of both SIP1 and ZEB1, but not either alone, by their specific siRNAs completely abolished TGF-β-induced E-cadherin repression. However, mesenchymal markers, including fibronectin, N-cadherin and vimentin, were not affected by knock-down of SIP1 and ZEB1. TGF-β induced the expression of Ets1, which in turn activated the ZEB1 promoter activity. Moreover, upregulation of SIP1 and ZEB1 by TGF-β was suppressed by knock-down of Ets1 expression. In addition, Id2 suppressed the TGF-β- and Ets1-induced upregulation of ZEB1. Taken together, these findings suggest that δEF-1 family proteins, SIP1 and ZEB1, are required, but not sufficient, for TGF-β-induced EMT, and that Ets1 induced by TGF-β may serve as an upstream transcriptional regulator of SIP1 and ZEB1.

转化生长因子β诱导小鼠乳腺NMuMG上皮细胞发生上皮-间充质转化，是肿瘤进展和胚胎发育过程中的重要事件。据报道，ID蛋白可以抑制转化生长因子-β诱导的子宫内膜转化的主要特征。在本研究中，我们发现δEF-1家族蛋白ZEB1和SIP1在转化生长因子β作用下的表达逐渐增加，其表达谱与E-钙粘蛋白的表达谱呈倒数关系。SIP1或ZEB1通过直接与E-钙粘蛋白启动子结合，显著下调NMuMG细胞中E-钙粘蛋白的转录。通过siRNA沉默SIP1和ZEB1的表达，但不能单独抑制两者的表达，可完全消除转化生长因子-β诱导的E-钙粘素抑制。然而，间充质标志物，包括纤维连接蛋白、N-钙粘蛋白和波形蛋白，不受SIP1和ZEB1基因敲除的影响。转化生长因子β诱导Ets1的表达，进而激活ZEB1启动子的活性。此外，转化生长因子-β对SIP1和ZEB1表达的上调可通过下调Ets1的表达来抑制。此外，Id2抑制转化生长因子-β-1和Ets1诱导的ZEB1表达上调。综上所述，这些发现提示δEF-1家族蛋白SIP1和ZEB1是β-β诱导的子宫内膜转化所必需的，但不是充分的，并且由转化生长因子诱导的ETS1可能作为SIP1和ZEB1的上游转录调节因子。