Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation
Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation
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DOI：
10.1101/gad.276304
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发表时间：
2004-01-01
影响因子：
10.5
通讯作者：
de la Pompa, JL
中科院分区：
文献类型：
--
作者：
Timmerman, LA;Grego-Bessa, J;de la Pompa, JL
上皮-间质转化（EMT）是胚胎发生和肿瘤转移的基础。Notch细胞间信号传导途径在后生动物进化过程中调节细胞命运决定，激活等位基因的过表达在哺乳动物中是致癌的。在这里，我们证明了Notch活性通过Snail阻遏物的转录诱导促进心脏发育和致癌转化过程中的EMT，Snail阻遏物是许多组织和肿瘤类型中EMT的有效和进化上保守的介体。在胚胎心脏中，Notch通过侧向诱导来促进选择性转化生长因子-β（TGF β）介导的EMT，其导致发育中的心脏瓣膜原基的细胞化。缺乏Notch信号传导元件的胚胎表现出严重减弱的心脏蜗牛表达，细胞间内皮细胞粘附复合物的异常维持，以及体内和体外的流产内皮细胞EMT。因此，激活的Notch 1（N1 IC）在斑马鱼胚胎中的瞬时异位表达导致细胞过多的心脏瓣膜，而Notch抑制阻止瓣膜发育。N1 IC在体外永生化内皮细胞中的过表达诱导EMT伴随着致癌转化，相应地诱导蜗牛和VE-钙粘蛋白表达的抑制。Notch在发生EMT的胚胎区域中表达，这表明Notch具有密切和基本的作用，其可能在肿瘤转移期间被重新激活。
Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-beta (TGFbeta)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis.