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A Double-Negative Feedback Loop between ZEB1-SIP1 and the microRNA-200 Family Regulates Epithelial-Mesenchymal Transition

¹ Hanson Institute, Institute of Medical and Veterinary Science and ² Discipline of Medicine, The University of Adelaide, Adelaide, Australia; and ³ Division of Molecular Bioscience, John Curtin School of Medical Research, The Australian National University, Canberra, Australia

Requests for reprints: Gregory Goodall, Hanson Institute, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia. Phone: 0061-88222-3430; Fax: 0061-88232-4092; E-mail: greg.goodall{at}imvs.sa.gov.au.

Key Words: microRNA • transcription • ZEB • feedback • epithelial-mesenchymal transition

Epithelial to mesenchymal transition occurs during embryologic development to allow tissue remodeling and is proposed to be a key step in the metastasis of epithelial-derived tumors. The miR-200 family of microRNAs plays a major role in specifying the epithelial phenotype by preventing expression of the transcription repressors, ZEB1/EF1 and SIP1/ZEB2. We show here that miR-200a, miR-200b, and the related miR-429 are all encoded on a 7.5-kb polycistronic primary miRNA (pri-miR) transcript. We show that the promoter for the pri-miR is located within a 300-bp segment located 4 kb upstream of miR-200b. This promoter region is sufficient to confer expression in epithelial cells and is repressed in mesenchymal cells by ZEB1 and SIP1 through their binding to a conserved pair of ZEB-type E-box elements located proximal to the transcription start site. These findings establish a double-negative feedback loop controlling ZEB1-SIP1 and miR-200 family expression that regulates cellular phenotype and has direct relevance to the role of these factors in tumor progression. [Cancer Res 2008;68(19):7846–54]