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The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1

Abstract

Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) and miR-205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)-β or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR-200 family alone was sufficient to prevent TGF-β-induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 (also known as δEF1) and SIP1 (also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition (MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR-200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.

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Figure 1: Identification of microRNAs that are regulated during EMT.
Figure 2: The miRNA-200 family and miRNA-205 are downregulated during TGF-β-mediated EMT.
Figure 3: ZEB1 and SIP1 3´UTRs are regulated by miR-200a, miR-200b and miR-205.
Figure 4: Manipulation of the miR-200 family and miR-205 levels can induce EMT or MET.
Figure 5: MicroRNA levels are associated with mesenchymal phenotype.

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Acknowledgements

The authors thank Don Newgreen for critical reading of the manuscript, Witold Filipowicz for the pCI-neo-hRL and RL-let-7 plasmids, Scott Hammond for the pLenti4.1EX plasmid, Mark van der Hoek and the Adelaide Microarray Facility for printing of the microarrays, and members of the Goodall and Khew-Goodall laboratories for helpful discussions. This work was supported by grants from the National Health and Medical Research Council of Australia (to Y. K.-G., M. A. V. and G. J. G.) and The Cancer Council South Australia (to G. J. G.). P. A. G. is supported by a Peter Doherty Training Fellowship from the National Health and Medical Research Council of Australia.

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Correspondence to Gregory J. Goodall.

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Supplementary Figures S1, S2, S3, S4, S5 and Supplementary Table 1 (PDF 1400 kb)

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Gregory, P., Bert, A., Paterson, E. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10, 593–601 (2008). https://doi.org/10.1038/ncb1722

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