Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis.
Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis.
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DOI：
10.1158/0008-5472.can-10-2330
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Casas E;Kim J;Bendesky A;Ohno-Machado L;Wolfe CJ;Yang J
为了转移，癌细胞必须减弱细胞间粘附以扩散到远处器官。一组转录因子，包括Twist 1，Snail 1，Snail 2，ZEB 1和ZEB 2，已被证明可诱导上皮-间充质转化（EMT），从而促进肿瘤扩散。然而，目前还不清楚这些转录因子是否独立或协调激活EMT程序的功能。在这里，我们报告说，直接诱导蜗牛2是必不可少的Twist 1诱导EMT。Snail 2敲除完全阻断Twist 1抑制E-钙粘蛋白转录的能力。Twist 1与邻近Snail 2启动子上进化上保守的E-box结合以诱导其转录。Snail 2诱导对于Twist 1诱导的小鼠细胞侵袭和远处转移至关重要。在人类乳腺肿瘤中，Twist 1和Snail 2的表达高度相关。总之，我们的研究结果表明，Twist 1需要诱导Snail 2来抑制EMT程序的上皮分支，Twist 1和Snail 2共同作用以促进EMT和肿瘤转移。
To metastasize, carcinoma cells must attenuate cell-cell adhesion to disseminate into distant organs. A group of transcription factors, including Twist1, Snail1, Snail2, ZEB1, and ZEB2, have been shown to induce Epithelial-Mesenchymal Transition (EMT), thus promoting tumor dissemination. However, it is unknown whether these transcription factors function independently or coordinately to activate the EMT program. Here we report that direct induction of Snail2 is essential for Twist1 to induce EMT. Snail2 knockdown completely blocks the ability of Twist1 to suppress E-cadherin transcription. Twist1 binds to an evolutionarily conserved E-box on the proximate Snail2 promoter to induce its transcription. Snail2 induction is essential for Twist1-induced cell invasion and distant metastasis in mice. In human breast tumors, the expression of Twist1 and Snail2 is highly correlated. Together, our results show that Twist1 needs to induce Snail2 to suppress the epithelial branch of the EMT program and that Twist1 and Snail2 act together to promote EMT and tumor metastasis.