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

Philip Gregory, Cameron Bracken, Eric Smith, Andrew Bert, Josephine Wright, Suraya Roslan, Melanie Morris, Leila Wyatt, Gelareh Farshid, Yat-Yuen Lim, Geoffrey Lindeman, M Frances Shannon, Paul Drew, Yeesim Khew-Goodall, Gregory Goodall

Research output: Contribution to journalArticle

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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 - 2011

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Epithelial-Mesenchymal Transition
Transforming Growth Factors
Transforming Growth Factor beta
Maintenance
Epithelial Cells
Ductal Carcinoma
Madin Darby Canine Kidney Cells
Homeobox Genes
Zinc Fingers
DNA Methylation
Embryonic Development
Transcription Factors
Breast Neoplasms
Neoplasm Metastasis
Phenotype
Cell Line
Neoplasms

Cite this

Gregory, Philip ; Bracken, Cameron ; Smith, Eric ; Bert, Andrew ; Wright, Josephine ; Roslan, Suraya ; Morris, Melanie ; Wyatt, Leila ; Farshid, Gelareh ; Lim, Yat-Yuen ; Lindeman, Geoffrey ; Shannon, M Frances ; Drew, Paul ; Khew-Goodall, Yeesim ; Goodall, Gregory. / An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. In: Molecular Biology of the Cell. 2011 ; Vol. 22, No. 10. pp. 1686-1698.
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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",
author = "Philip Gregory and Cameron Bracken and Eric Smith and Andrew Bert and Josephine Wright and Suraya Roslan and Melanie Morris and Leila Wyatt and Gelareh Farshid and Yat-Yuen Lim and Geoffrey Lindeman and Shannon, {M Frances} and Paul Drew and Yeesim Khew-Goodall and Gregory Goodall",
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Gregory, P, Bracken, C, Smith, E, Bert, A, Wright, J, Roslan, S, Morris, M, Wyatt, L, Farshid, G, Lim, Y-Y, Lindeman, G, Shannon, MF, Drew, P, Khew-Goodall, Y & Goodall, G 2011, 'An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition', Molecular Biology of the Cell, vol. 22, no. 10, pp. 1686-1698. https://doi.org/10.1091/mbc.E11-02-0103

An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. / Gregory, Philip; Bracken, Cameron; Smith, Eric; Bert, Andrew; Wright, Josephine; Roslan, Suraya; Morris, Melanie; Wyatt, Leila; Farshid, Gelareh; Lim, Yat-Yuen; Lindeman, Geoffrey; Shannon, M Frances; Drew, Paul; Khew-Goodall, Yeesim; Goodall, Gregory.

In: Molecular Biology of the Cell, Vol. 22, No. 10, 2011, p. 1686-1698.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition

AU - Gregory, Philip

AU - Bracken, Cameron

AU - Smith, Eric

AU - Bert, Andrew

AU - Wright, Josephine

AU - Roslan, Suraya

AU - Morris, Melanie

AU - Wyatt, Leila

AU - Farshid, Gelareh

AU - Lim, Yat-Yuen

AU - Lindeman, Geoffrey

AU - Shannon, M Frances

AU - Drew, Paul

AU - Khew-Goodall, Yeesim

AU - Goodall, Gregory

PY - 2011

Y1 - 2011

N2 - 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

AB - 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

U2 - 10.1091/mbc.E11-02-0103

DO - 10.1091/mbc.E11-02-0103

M3 - Article

VL - 22

SP - 1686

EP - 1698

JO - Cell regulation

JF - Cell regulation

SN - 1044-2030

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ER -