A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cells

作者：Ulrike Burk, Jörg Schubert, Ulrich F. Wellner, Otto Schmalhofer, Elizabeth Vincan, Simone Spaderna, Thomas Brabletz · 发表于：EMBO Reports · 年份：2008 · DOI：10.1038/embor.2008.74 · 被引用次数：1726 · 研究领域：MicroRNA in disease regulation、RNA modifications and cancer、Cancer-related molecular mechanisms research

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 beta2 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.