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Cell Signal. 2016 Aug;28(8):861-70. doi: 10.1016/j.cellsig.2016.03.002. Epub 2016 Mar 19.

Autocrine TGF-β/ZEB/microRNA-200 signal transduction drives epithelial-mesenchymal transition: Kinetic models predict minimal drug dose to inhibit metastasis.

Author information

1
Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany; Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany. Electronic address: katja.rateitschak@uni-greifswald.de.
2
Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany.
3
Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany; Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Center at Stellenbosch University, Marais Street, Stellenbosch 7600, South Africa.
4
Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, 18057 Rostock, Germany.

Abstract

The epithelial-mesenchymal transition (EMT) is the crucial step that cancer cells must pass before they can undergo metastasis. The transition requires the activity of complex functional networks that downregulate properties of the epithelial phenotype and upregulate characteristics of the mesenchymal phenotype. The networks frequently include reciprocal repressions between transcription factors (TFs) driving the EMT and microRNAs (miRs) inducing the reverse process, termed mesenchymal-epithelial transition (MET). In this work we develop four kinetic models that are based on experimental data and hypotheses describing how autocrine transforming growth factor-β (TGF-β) signal transduction induces and maintains an EMT by upregulating the TFs ZEB1 and ZEB2 which repress the expression of the miR-200b/c family members. After successful model calibration we validate our models by predicting requirements for the maintenance of the mesenchymal steady state which agree with experimental data. Finally, we apply our validated kinetic models for the design of experiments in cancer therapy. We demonstrate how steady state properties of the kinetic models, combined with data from tumor-derived cell lines of individual patients, can predict the minimal amount of an inhibitor to induce a MET.

KEYWORDS:

Design of experiments; Epithelial-mesenchymal transition; Interaction between ZEB and microRNA-200; Kinetic model; Metastasis inhibition

PMID:
27000495
DOI:
10.1016/j.cellsig.2016.03.002
[Indexed for MEDLINE]

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