区分EMT三稳性的机理
Distinguishing Mechanisms Underlying EMT Tristability
摘要：
背景资料：上皮-间充质转化（EMT）使类上皮细胞在胚胎发育和组织修复过程中具有增强的迁移能力。EMT还可以被癌细胞吸收以获得转移潜能和耐药性。最近的研究认为，上皮（E）细胞可以经历部分EMT以获得通常显示集体迁移的混合上皮/间充质（E/M）表型，或者经历完全EMT以采用显示个体迁移的间充质（M）表型。EMT的核心调控网络- miR-34/SNAIL/miR-200/ZEB 1-已被各种研究所确定，但该网络如何调控E、E/M和M表型之间的转换仍存在争议。两个主要的数学模型-三元嵌合开关（TCS）和级联开关（CBS）-都集中在miR-34/SNAIL/miR-200/ZEB 1网络，已被提出来阐明EMT动力学，但这两个模型中的一个或两个如何捕捉最近的实验观察EMT动力学的详细分析仍然有待完成。结果如下：在这里，通过一个综合的实验和理论方法，我们首先表明，这两个模型都可以用来理解EMT-E-E/M-M的两步转变，SNAIL和ZEB 1对外源性TGF-β的不同反应和完全EMT的不可逆性。接下来，我们提出了新的实验结果，往往区分这两种模型。我们表明，ZEB 1是目前在混合E/M H1975细胞中的中间水平，并在HMLE细胞，SNAIL的过表达是不足以启动EMT的ZEB 1和FOXC 2的情况下。结论：这些实验结果支持TCS模型，该模型提出miR-200/ZEB 1作为三向决策开关，使E、混合E/M和M表型之间的转换成为可能。
英文摘要：
Background: The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models - ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done. Results: Here, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E-E/M-M, the different responses of SNAIL and ZEB1 to exogenous TGF-b and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2. Conclusions: These experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes.
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