Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence.
Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence.
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DOI：
10.1158/1541-7786.mcr-11-0371
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发表时间：
2011-12
期刊：
影响因子：
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通讯作者：
Longmore GD
中科院分区：
文献类型：
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作者：
Tran DD;Corsa CA;Biswas H;Aft RL;Longmore GD
上皮-间充质转化(EMT)是一种正常的发育过程，也被认为在癌症转移中起着重要作用。EMT的最终诱导物是转录抑制因子，它们可以单独诱导实验性EMT，但在许多细胞中，特别是在癌细胞中，多种诱导物同时表达。他们为什么、会不会以及如何相互作用来监管EMT，目前还没有答案。使用RNA干扰技术来影响蛋白质的过度表达和避免潜在的过度表达伪影，再加上瞬时的转化生长因子β治疗，以便更好地模拟体内的条件，我们证明，在非致瘤和致瘤的上皮癌细胞中，Snail1是启动EMT所唯一需要的，而Twist1是维持晚期EMT所必需的。Twist1存在于静止的上皮细胞中，对于EMT的启动是必不可少的。从机制上讲，在瞬时转化生长因子β作用下，瞬时Snail1的表达直接抑制Twist1的转录，随后随着Snail1水平的降低，Twist1的转录上调，以维持E-钙粘附素的下调和EMT的生长停止。持续的Twist1表达与p38和ERK信号反馈环有关，该环维持静止微转移肿瘤特有的生长抑制信号。这种Snail1-Twist1的时空协作也在活体内观察到，在人类乳腺癌进展到转移的过程中。在播散性微转移的骨髓肿瘤细胞中，Twist1的水平，而不是Snail1的水平，以及Twist1：Snail1的比率被发现与生存和治疗耐药有关，并且对转移或复发有很高的预测价值。
Epithelial-Mesenchymal Transition (EMT) is a normal developmental program that is considered to also play an important role in cancer metastasis. Ultimate inducers of EMT are transcriptional repressors that individually can induce experimental EMT, yet in many cells, particularly cancer cells, multiple inducers are expressed simultaneously. Why, and if and how they interact to regulate EMT is unanswered. Using RNAi technology to effect protein knockdown and avoid potential over-expression artifact coupled with transient TGFβ treatment to better mimic in vivo conditions we show, in both non-tumorigenic and tumorigenic epithelial cancer cells, that Snail1 is uniquely required for EMT initiation, while Twist1 is required to maintain late EMT. Twist1, present in resting epithelial cells, is dispensable for EMT initiation. Mechanistically, in response to transient TGFβ treatment, transient Snail1 expression represses Twist1 transcription directly, which is subsequently upregulated, as Snail1 levels decrease, to sustain E-cadherin downregulation and growth arrest of EMT. Persistent Twist1 expression is associated with a p38 and ERK signal feedback loop that sustains growth-inhibitory signals characteristic of quiescent micrometastatic tumors. This Snail1-Twist1 temporal and spatial cooperation was also observed in vivo during human breast cancer progression to metastasis. Twist1 level, but not Snail1 level, and Twist1:Snail1 ratio in disseminated micrometastatic bone marrow tumor cells was found to correlate with survival and treatment resistance, and is highly predictive of metastatic or recurrent disease.