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A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cells
Author(s) -
Burk Ulrike,
Schubert Jörg,
Wellner Ulrich,
Schmalhofer Otto,
Vincan Elizabeth,
Spaderna Simone,
Brabletz Thomas
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.74
Subject(s) - homeobox , epithelial–mesenchymal transition , biology , microrna , cancer research , transcription factor , repressor , psychological repression , zinc finger , metastasis , microbiology and biotechnology , pancreatic cancer , cancer cell , embryonic stem cell , cancer , gene , genetics , gene expression
The embryonic programme ‘epithelial–mesenchymal transition’ (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc‐finger E‐box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA‐200 family members miR‐141 and miR‐200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor β2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA‐mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers.