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

TLDR

Epithelial‑mesenchymal transition drives tissue remodeling in development and is implicated in metastasis, while the miR‑200 family maintains epithelial identity by suppressing the transcriptional repressors ZEB1 and SIP1. The authors identified a 300‑bp promoter upstream of the pri‑miR that drives expression in epithelial cells but is repressed in mesenchymal cells through ZEB1 and SIP1 binding to adjacent E‑box elements. They demonstrated that miR‑200a, miR‑200b, and miR‑429 are transcribed from a single 7.5‑kb pri‑miR, and that this promoter establishes a double‑negative feedback loop with ZEB1‑SIP1 that governs cellular phenotype and tumor progression. Cancer Res 2008;68(19):7846–54.

Abstract

Abstract 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/δEF1 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]