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首页> 外文期刊>Molecular and Cellular Biology >A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis
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A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis

机译：TrkB诱导的上皮-间质转化样转化，失语抵抗和转移的关键的扭曲蜗牛轴。

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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.
机译：在全基因组转移基因的无基因抑制筛选中，我们先前鉴定了神经营养性受体酪氨酸激酶TrkB。在小鼠异种移植物中，活化的TrkB引起高度侵袭性和转移性肿瘤。在这里，我们描述了TrkB还诱导了强烈的形态转化，类似于上皮-间质转化（EMT）。这需要TrkB激酶活性，功能性促分裂原激活的蛋白激酶途径，抑制E-钙粘蛋白和诱导Twist（一种有助于EMT和转移的转录因子）的诱导。 RNA干扰（RNAi）介导的Twist耗竭阻止TrkB诱导的EMT样转化，无神经抑制和肿瘤异种移植物的生长。通过寻找TrkB-Twist信号转导的重要效应子，我们发现Twist诱导了Snail，这是另一种与不良预后相关的EMT调节剂。蜗牛耗竭削弱了TrkB诱导的EMT样转化和神经抑制，但与Twist耗竭相反，它未能抑制肿瘤的生长。取而代之的是，Snail RNAi特别损害了肺转移的形成。上位性实验表明，Twist在Snail的上游起作用。我们的结果表明，TrkB信号激活了Twist-Snail轴，该轴与EMT样转化，肿瘤发生和转移密切相关。此外，我们的数据进一步揭示了Twist和Snail（EMT和转移的两个关键转录调节因子）之间的上位关系。

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