The ZEB1/miR-200c feedback loop regulates invasion via actin interacting proteins MYLK and TKS5
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Vignesh Sundararajan1,2,3,*, Nicolas Gengenbacher4,*, Marc P. Stemmler5, Julia A. Kleemann5, Thomas Brabletz5, Simone Brabletz5
1Department of Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany
2Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany
3Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany
4Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
5Department of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Erlangen, Germany
*These authors have contributed equally to this work
Simone Brabletz, e-mail: [email protected]
Keywords: epithelial to mesenchymal transition (EMT), ZEB1, miR-200, MYLK (MLCK), invadopodia
Received: July 03, 2015 Accepted: August 07, 2015 Published: August 20, 2015
Epithelial to mesenchymal transition (EMT) is a developmental process which is aberrantly activated during cancer invasion and metastasis. Elevated expression of EMT-inducers like ZEB1 enables tumor cells to detach from the primary tumor and invade into the surrounding tissue. The main antagonist of ZEB1 in controlling EMT is the microRNA-200 family that is reciprocally linked to ZEB1 in a double negative feedback loop. Here, we further elucidate how the ZEB1/miR-200 feedback loop controls invasion of tumor cells. The process of EMT is attended by major changes in the actin cytoskeleton. Via in silico screening of genes encoding for actin interacting proteins, we identified two novel targets of miR-200c - TKS5 and MYLK (MLCK). Co-expression of both genes with ZEB1 was observed in several cancer cell lines as well as in breast cancer patients and correlated with low miR-200c levels. Depletion of TKS5 or MYLK in breast cancer cells reduced their invasive potential and their ability to form invadopodia. Whereas TKS5 is known to be a major component, we could identify MYLK as a novel player in invadopodia formation. In summary, TKS5 and MYLK represent two mediators of invasive behavior of cancer cells that are regulated by the ZEB1/miR-200 feedback loop.
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