Abstract
Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional _targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.
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Acknowledgements
We thank Gabriele Stengl and Peter Steinlein, Institute of Molecular Pathology, Vienna, for Flow Cytometry (FACS) experiments. Furthermore, we thank Jürgen Pollheimer and Martin Knofler for their technical expertise in transpore migration assays and Heidemarie Huber for support in immunohistochemistry. This study was supported by funds from the Hochschuljubiläumsstiftung of the city of Vienna to AE (H-703/2005), by grants from the Austrian Science Research Fund (FWF) No. SFB 006 to RF (603) and HB (612), SFB-F28 to WM and by funds of the Austrian Ministry of Education, Science, and the Arts (Austrian Genome Research Program GEN-AU) to MS, WS, NS, AW. AS is supported by the ÖAD-Pakistan Scholarship programme.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Aigner, K., Dampier, B., Descovich, L. et al. The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26, 6979–6988 (2007). https://doi.org/10.1038/sj.onc.1210508
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DOI: https://doi.org/10.1038/sj.onc.1210508
