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

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, Geoff Lindeman, M Frances Shannon, Paul Drew, Yeesim Khew-Goodall, Gregory Goodall

    Research output: Contribution to journalArticle

    369 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1686-1698
    Number of pages13
    JournalMolecular Biology of the Cell
    Volume22
    Issue number10
    DOIs
    Publication statusPublished - 15 May 2011

    Fingerprint Dive into the research topics of 'An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition'. Together they form a unique fingerprint.

  • Cite this

    Gregory, P. A., Bracken, C. P., Smith, E., Bert, A. G., Wright, J. A., Roslan, S., Morris, M., Wyatt, L., Farshid, G., Lim, Y-Y., Lindeman, G., Shannon, M. F., Drew, P., Khew-Goodall, Y., & Goodall, G. (2011). An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Molecular Biology of the Cell, 22(10), 1686-1698. https://doi.org/10.1091/mbc.E11-02-0103