Systems biology approach suggests new miRNAs as phenotypic stability factors in the epithelial–mesenchymal transition
Daner A. Silveira, Shantanu Gupta, José C. M. Mombach
Abstract
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.