A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis
A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis
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DOI：
10.1128/mcb.01164-08
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Peeper, Daniel S.
中科院分区：
文献类型：
--
作者：
Smit, Marjon A.;Geiger, Thomas R.;Peeper, Daniel S.
在转移基因的全基因组anoikis抑制筛选中，我们先前确定了神经营养受体酪氨酸激酶TrkB。在小鼠异种移植物中，激活的TrkB引起高度侵袭性和转移性肿瘤。在这里，我们描述了TrkB也诱导强烈的形态转化，类似于上皮-间质转化（EMT）。这需要TrkB激酶活性，一种功能性有丝分裂原激活的蛋白激酶途径，抑制E-cadherin，并诱导Twist，一种促进EMT和转移的转录因子。RNA干扰（RNAi）介导的Twist耗尽阻断了trkb诱导的emt样转化、anoikis抑制和肿瘤异种移植物的生长。通过寻找TrkB-Twist信号的基本效应因子，我们发现Twist诱导另一种与癌症预后不良相关的EMT调控因子Snail。蜗牛耗尽损害了TrkB诱导的emt样转化和anoikis抑制，但与Twist耗尽相比，它未能抑制肿瘤生长。相反，Snail RNAi特异性地破坏了肺转移灶的形成。上位实验表明，Twist作用于Snail的上游。我们的研究结果表明，TrkB信号激活了Twist-Snail轴，该轴在emt样转化、肿瘤发生和转移中起关键作用。此外，我们的数据揭示了Twist和Snail之间的上位性关系，这是EMT和转移的两个关键转录调节因子。
In a genomewide anoikis suppression screen for metastasis genes, we previously identified the neurotrophic receptor tyrosine kinase TrkB. In mouse xenografts, activated TrkB caused highly invasive and metastatic tumors. Here, we describe that TrkB also induces a strong morphological transformation, resembling epithelial-mesenchymal transition (EMT). This required TrkB kinase activity, a functional mitogen-activated protein kinase pathway, suppression of E-cadherin, and induction of Twist, a transcription factor contributing to EMT and metastasis. RNA interference (RNAi)-mediated Twist depletion blocked TrkB-induced EMT-like transformation, anoikis suppression, and growth of tumor xenografts. By searching for essential effectors of TrkB-Twist signaling, we found that Twist induces Snail, another EMT regulator associated with poor cancer prognosis. Snail depletion impaired EMT-like transformation and anoikis suppression induced by TrkB, but in contrast to Twist depletion, it failed to inhibit tumor growth. Instead, Snail RNAi specifically impaired the formation of lung metastases. Epistasis experiments suggested that Twist acts upstream from Snail. Our results demonstrate that TrkB signaling activates a Twist-Snail axis that is critically involved in EMT-like transformation, tumorigenesis, and metastasis. Moreover, our data shed more light on the epistatic relationship between Twist and Snail, two key transcriptional regulators of EMT and metastasis.