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https://hdl.handle.net/2440/65624
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Type: | Journal article |
Title: | An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition |
Other Titles: | An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition |
Author: | Gregory, P. Bracken, C. Smith, E. Bert, A. Wright, J. Roslan, S. Morris, M. Belle, L. Farshid, G. Lim, Y. Lindeman, G. Shannon, F. Drew, P. Khew-Goodall, Y. Goodall, G. |
Citation: | Molecular Biology of the Cell, 2011; 22(10):1686-1698 |
Publisher: | Amer Soc Cell Biology |
Issue Date: | 2011 |
ISSN: | 1059-1524 1939-4586 |
Editor: | Bronner-Fraser, M. |
Statement of Responsibility: | Philip A. Gregory, Cameron P. Bracken, Eric Smith, Andrew G. Bert, Josephine A. Wright, Suraya Roslan, Melanie Morris, Leila Wyatt, Gelareh Farshid, Yat-Yuen Lim, Geoffrey J. Lindeman, M. Frances Shannon, Paul A. Drew, Yeesim Khew-Goodall and Gregory J. Goodall |
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-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β 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-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers. |
Keywords: | Cell Line Animals Dogs Humans Carcinoma, Ductal, Breast Breast Neoplasms Transforming Growth Factor beta Homeodomain Proteins Transcription Factors Repressor Proteins MicroRNAs Autocrine Communication Signal Transduction DNA Methylation Up-Regulation Female Cofilin 2 Feedback, Physiological Epithelial-Mesenchymal Transition Zinc Finger E-box-Binding Homeobox 1 Zinc Finger E-box Binding Homeobox 2 |
Rights: | © 2011 Gregory et al. This article is distributed by The American Society for Cell Biology under license from the author(s). |
DOI: | 10.1091/mbc.E11-02-0103 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.1091/mbc.e11-02-0103 |
Appears in Collections: | Aurora harvest 5 Microbiology and Immunology publications |
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