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J. Biol. Chem., Vol. 283, Issue 22, 14910-14914, May 30, 2008

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The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2^*

From the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in which step(s) of the multistep metastatic cascade these miRNAs play a defined functional role. To study the functional importance of miRNAs in epithelial-mesenchymal transition (EMT), a process thought to initiate metastasis by enhancing the motility of tumor cells, we used a well established in vitro EMT assay: transforming growth factor-β-induced EMT in NMuMG murine mammary epithelial cells. We found that members of the miR-200 family, organized as two clusters in the genome, were repressed during EMT. Overexpression of each miRNA individually or as clusters in NMuMG cells hindered EMT by enhancing E-cadherin expression through direct targeting of ZEB1 and ZEB2, which encode transcriptional repressors of E-cadherin. In the 4TO7 mouse carcinoma cell line, which expresses low levels of endogenous E-cadherin and displays a mesenchymal phenotype, ectopic expression of the miR-200 family miRNAs significantly increased E-cadherin expression and altered cell morphology to an epithelial phenotype. Furthermore, ectopic expression of each miR-200 miRNA cluster significantly reduced the in vitro motility of 4TO7 cells in migration assays. These results suggested that loss of expression of the miR-200 family members may play a critical role in the repression of E-cadherin by ZEB1 and ZEB2 during EMT, thereby enhancing migration and invasion during cancer progression.

Received for publication, April 8, 2008 , and in revised form, April 14, 2008.

^* This work was supported by the U.S. Army Medical Research and Material Command (Grant W81XWH-06-1-0481) with additional support from the American Cancer Society (Grant RSG MGO-110765), and the Susan G. Komen Foundation (Grant BCTR0503765). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Natural Sciences and Engineering Research Council of Canada.

² Supported by a fellowship from the New Jersey Commission of Cancer Research.

³ To whom correspondence should be addressed: Dept. of Molecular Biology, Washington Rd., LTL 255, Princeton University, Princeton, NJ 08544. Tel.: 609-258-8834; E-mail: ykang{at}princeton.edu.

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