The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity
Kirsten Aigner,Brigitta Dampier,L Descovich,Mario Mikula,Aneesa Sultan,Martin Schreiber,Wolfgang Mikulits,Thomas Brabletz,Dennis Strand,P Obrist,Wolfgang Sommergruber,Norbert Schweifer,Andreas Wernitznig,Hartmut Beug,Roland Foisner,Andreas Eger +15 more
TLDR
The data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression, and downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro.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.read more
Citations
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Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis
Jing Yang,Robert A. Weinberg +1 more
TL;DR: This review summarizes and compares major signaling pathways that regulate the epithelial-mesenchymal transitions during both development and tumor metastasis and examines their role in carcinoma invasion and metastasis.
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TGF-beta-induced epithelial to mesenchymal transition.
TL;DR: The induction of EMT in response to TGF-β is discussed, and the underlying signaling and transcription mechanisms are focused on.
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The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2
TL;DR: In this article, the miR-200 miRNA family was found to directly target the mRNA of the E-cadherin transcriptional repressors ZEB1 (TCF8/δEF1) and ZEB2 (SMAD-interacting protein 1 [SIP1]/ZFXH1B).
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New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer
TL;DR: It is highlighted how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state which could function as cancer stem cells, and its effects on the immunobiology of carcinomas.
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A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells
Ulrike Burk,Joerg Schubert,Ulrich F. Wellner,Otto Schmalhofer,Elizabeth Vincan,Simone Spaderna,Thomas Brabletz +6 more
TL;DR: Results indicate that ZEB1 triggers an microRNA‐mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells, and thus explain the strong intratumorous heterogeneity observed in many human cancers.
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