Combinatorial Cooperativity in miR200-Zeb Feedback Network can Control Epithelial-Mesenchymal Transition.

IF 2 4区 数学 Q2 BIOLOGY
Mubasher Rashid, Brasanna M Devi, Malay Banerjee
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引用次数: 0

Abstract

Carcinomas often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies report SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by placing cancer cells in at least three phenotypic states, viz. epithelial (E), hybrid (h-E/M), mesenchymal (M), along the E-M phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that the miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, h-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences-the circuit can dynamically switch between two (E, M) and three (E, h-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translation inhibition due to miR200 are essential for the occurrence of intermediate h-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to h-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.

miR200-Zeb 反馈网络中的组合合作可控制上皮-间充质转化
癌症通常利用上皮-间质转化(EMT)程序来促进癌症进展和转移。许多研究报告称,SNAIL诱导的miR200/Zeb反馈回路是调控EMT的关键,它可将癌细胞置于至少三种表型状态,即上皮(E)、混合(h-E/M)和间充质(M),并沿着E-M表型谱。然而,对于这种微小回路如何控制癌细胞进入和停留在各种状态,目前还缺乏分子层面的一致认识。在这里,我们利用分子结合数据和数学建模报告了 miR200/Zeb 电路基本上可以利用组合合作性来控制 E-M 表型的可塑性。我们确定了产生 E、h-E/M 和 M 表型的最小组合合作性。我们表明,破坏 Zeb 上特定数量的 miR200 结合位点以及 miR200 上的 Zeb 结合位点会产生表型后果--电路可在两种(E、M)和三种(E、h-E/M、M)表型之间动态切换。此外,我们还报告说,在 SNAIL 诱导的和 SNAIL 基因敲除的 miR200/Zeb 循环中,Zeb 的合作转录反馈以及 miR200 对 Zeb 翻译的抑制是出现中间 h-E/M 表型的关键。最后,我们证明了 SNAIL 对 EMT 可有可无,而在 SNAIL 缺失的情况下,转录反馈可控制细胞状态从 E 到 h-E/M 再到 M 的转变。因此,我们的研究结果突显了 miR200/Zeb 环路对 EMT 的分子水平调控,我们期待这些发现对未来旨在防止 EMT 促进的癌细胞扩散的努力至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.90
自引率
8.60%
发文量
123
审稿时长
7.5 months
期刊介绍: The Bulletin of Mathematical Biology, the official journal of the Society for Mathematical Biology, disseminates original research findings and other information relevant to the interface of biology and the mathematical sciences. Contributions should have relevance to both fields. In order to accommodate the broad scope of new developments, the journal accepts a variety of contributions, including: Original research articles focused on new biological insights gained with the help of tools from the mathematical sciences or new mathematical tools and methods with demonstrated applicability to biological investigations Research in mathematical biology education Reviews Commentaries Perspectives, and contributions that discuss issues important to the profession All contributions are peer-reviewed.
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