A Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition.
A Theoretical Model of the Wnt Signaling Pathway in the Epithelial Mesenchymal Transition.
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DOI：
10.1186/s12976-017-0064-7
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发表时间：
2017-10-10
影响因子：
--
通讯作者：
Bhattacharya S
中科院分区：
文献类型：
--
作者：
Gasior K;Hauck M;Wilson A;Bhattacharya S
在形成原发性癌后，肿瘤细胞通过经历上皮间质转换（EMT）而转移，这是由炎症和基质细胞中的线索触发的，在微观环境中，EMT中会损失高度粘附的性质，并在类似于刺激性的外观上进行了行为。上皮和间质之间的能力切换表型控制EMT，即使在离开原发性肿瘤微环境并EMT诱导的细胞外信号之后，该细胞即使细胞可以保持其间充质表型。
这项工作介绍了EMT的简单数学模型，特别是四个关键蛋白在Wnt信号通路中扮演的角色：散乱（DVL），E-钙粘蛋白，β-catenin和Slug的模型预测，即在Wnt途径中激活wnt途径。表型一旦迁移到原发性肿瘤。在那它是由β-catenin诱导的，在存在足够量的Wnt配体的情况下，E-钙粘着蛋白水平对通过β-catenin与IC50 SLUG浓度的SLUG浓度的比率敏感。
电子钙蛋白对SLUG的降解率的敏感性，以及抑制E-钙粘蛋白产生所需的IC50 SLUG浓度，表明细胞的粘合性质如何取决于SLUG的细微调节，从而突出了β-catenin在EMT和SLECAD的激活中的作用，这是对EMT和SLUG依次的作用，这是对EMT和slug termiate and-cad蛋白的作用。灭活所必需的DVL GSK-3β复合物介导β-catenin降解，β-catenin易位到核的速率以及抑制E-钙粘蛋白产生的SLUG的IC50浓度。
本文的在线版本（10.1186/S12976-017-0064-7）包含补充材料，可供授权用户使用。
Following the formation of a primary carcinoma, neoplastic cells metastasize by undergoing the epithelial mesenchymal transition (EMT), which is triggered by cues from inflammatory and stromal cells in the microenvironment. EMT allows epithelial cells to lose their highly adhesive nature and instead adopt the spindle-like appearance, as well as the invasive and migratory behavior, of mesenchymal cells. We hypothesize that a bistable switch between the epithelial and mesenchymal phenotypes governs EMT, allowing the cell to maintain its mesenchymal phenotype even after it leaves the primary tumor microenvironment and EMT-inducing extracellular signal. This work presents a simple mathematical model of EMT, specifically the roles played by four key proteins in the Wnt signaling pathway: Dishevelled (Dvl), E-cadherin, β-catenin, and Slug. The model predicts that following activation of the Wnt pathway, an epithelial cell in the primary carcinoma must attain a threshold level of membrane-bound Dvl to convert to the mesenchymal-like phenotype and maintain that phenotype once it has migrated away from the primary tumor. Furthermore, sensitivity analysis of the model suggests that in both the epithelial and the mesenchymal states, the steady state behavior of E-cadherin and the transcription factor Slug are sensitive to changes in the degradation rate of Slug, while E-cadherin is also sensitive to the IC50 (half-maximal) concentration of Slug necessary to inhibit E-cadherin production. The steady state behavior of Slug exhibits sensitivity to changes in the rate at which it is induced by β-catenin upon activation of the Wnt pathway. In the presence of sufficient amount of Wnt ligand, E-cadherin levels are sensitive to the ratio of the rate of Slug activation via β-catenin to the IC50 concentration of Slug necessary to inhibit E-cadherin production. The sensitivity of E-cadherin to the degradation rate of Slug, as well as the IC50 concentration of Slug necessary to inhibit E-cadherin production, shows how the adhesive nature of the cell depends on finely-tuned regulation of Slug. By highlighting the role of β-catenin in the activation of EMT and the relationship between E-cadherin and Slug, this model identifies critical parameters of therapeutic concern, such as the threshold level of Dvl necessary to inactivate the GSK-3β complex mediating β-catenin degradation, the rate at which β-catenin translocates to the nucleus, and the IC50 concentration of Slug needed to inhibit E-cadherin production. The online version of this article (10.1186/s12976-017-0064-7) contains supplementary material, which is available to authorized users.
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