The epithelial–mesenchymal transition (EMT) is a cellular programme on which epithelial cells undergo a phenotypic transition to mesenchymal ones acquiring metastatic properties such as mobility and invasion. TGF-β signalling can promote the EMT process. However, the dynamics of the concentration response of TGF-β-induced EMT is not well explained. In this work, we propose a logical model of TGF-β dose dependence of EMT in MCF10A breast cells. The model outcomes agree with experimentally observed phenotypes for the wild-type and perturbed/mutated cases. As important findings of the model, it predicts the coexistence of more than one hybrid state and that the circuit between TWIST1 and miR-129 is involved in their stabilization. Thus, miR-129 should be considered as a phenotypic stability factor. The circuit TWIST1/miR-129 associates with ZEB1-mediated circuits involving miRNAs 200, 1199, 340, and the protein GRHL2 to stabilize the hybrid state. Additionally, we found a possible new autocrine mechanism composed of the circuit involving TGF-β, miR-200, and SNAIL1 that contributes to the stabilization of the mesenchymal state. Therefore, our work can extend our comprehension of TGF-β-induced EMT in MCF10A cells to potentially improve the strategies for breast cancer treatment.

中文翻译：

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系统生物学方法表明新的 miRNA 作为上皮 - 间质转化中的表型稳定因子

上皮-间充质转化 (EMT) 是一种细胞程序，在该程序上，上皮细胞经历表型转变为间充质细胞，获得转移特性，例如移动性和侵袭性。TGF-β 信号可以促进 EMT 过程。然而，TGF-β 诱导的 EMT 浓度响应的动力学并没有得到很好的解释。在这项工作中，我们提出了 MCF10A 乳腺细胞中 EMT 的 TGF-β 剂量依赖性的逻辑模型。模型结果与野生型和扰动/突变病例的实验观察表型一致。作为该模型的重要发现，它预测了一种以上混合状态的共存，并且 TWIST1 和 miR-129 之间的电路参与了它们的稳定。因此，应将 miR-129 视为表型稳定性因子。回路 TWIST1/miR-129 与 ZEB1 介导的回路相关联，这些回路涉及 miRNA 200、1199、340 和蛋白质 GRHL2，以稳定杂交状态。此外，我们发现了一种可能的新自分泌机制，由涉及 TGF-β、miR-200 和 SNAIL1 的回路组成，有助于稳定间充质状态。因此，我们的工作可以扩展我们对 MCF10A 细胞中 TGF-β 诱导的 EMT 的理解，以潜在地改进乳腺癌治疗策略。