An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition

Gregory, PA; Bracken, CP; Smith, E; Bert, AG; Wright, JA; Roslan, S; Morris, M; Wyatt, L; Farshid, G; Lim, YY; Lindeman, GJ; Shannon, MF; Drew, PA; Khew-Goodall, Y; Goodall, GJ

Author(s): Gregory, PA; Bracken, CP; Smith, E; Bert, AG; Wright, JA; Roslan, S; Morris, M; Wyatt, L; Farshid, G; Lim, YY; Lindeman, GJ; Shannon, MF; Drew, PA; Khew-Goodall, Y; Goodall, GJ;
Details: Publication Year 2011-05-15,Volume 22,Issue #10,Page 1686-1698
Journal Title: MOLECULAR BIOLOGY OF THE CELL
Publication Type: Journal Article
Abstract: Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-beta (TGF-beta) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-beta signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-beta/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-beta and negative correlations between miR-200 and TGF-beta and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-beta/ZEB/miR-200 signaling network being active in breast cancers.
Publisher: AMER SOC CELL BIOLOGY
Keywords: CANCER STEM-CELLS; TGF-BETA; E-CADHERIN; MIR-200 FAMILY; DNA METHYLATION; BREAST-CANCER; TRANSCRIPTIONAL REPRESSOR; TUMOR PROGRESSION; DOWN-REGULATION; FEEDBACK LOOP
Publisher's Version: https://doi.org/10.1091/mbc.E11-02-0103
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-05-15 12:00:00