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

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

doi:10.1091/mbc.e11-02-0103

Cited by 533 publications

(540 citation statements)

References 60 publications

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“…After EMT is complete, ZEB levels remain high (Fig. 6C); the cells maintain the stable mesenchymal state, in agreement with observations (37). Starting from this phenotype, the signal has to be reduced significantly below the basal level to allow for transitions back to the epithelial phenotype.…”

Section: Resultssupporting

confidence: 88%

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Jolly

Levine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

495

707

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Forward and backward transitions between epithelial and mesenchymal phenotypes play crucial roles in embryonic development and tissue repair. Aberrantly regulated transitions are also a hallmark of cancer metastasis. The genetic network that regulates these transitions appears to allow for the existence of a hybrid phenotype (epithelial/mesenchymal). Hybrid cells are endowed with mixed epithelial and mesenchymal characteristics, enabling specialized capabilities such as collective cell migration. Cell-fate determination between the three phenotypes is in fact regulated by a circuit composed of two highly interconnected chimeric modules-the miR-34/SNAIL and the miR-200/ZEB mutual-inhibition feedback circuits. Here, we used detailed modeling of microRNAbased regulation to study this core unit. More specifically, we investigated the functions of the two isolated modules and subsequently of the combined unit when the two modules are integrated into the full regulatory circuit. We found that miR-200/ZEB forms a tristable circuit that acts as a ternary switch, driven by miR-34/ SNAIL, that is a monostable module that acts as a noise-buffering integrator of internal and external signals. We propose to associate the three stable states-(1,0), (high miR-200)/(low ZEB); (0,1), (low miR-200)/(high ZEB); and (1/2,1/2), (medium miR-200)/(medium ZEB)-with the epithelial, mesenchymal, and hybrid phenotypes, respectively. Our (1/2,1/2) state hypothesis is consistent with recent experimental studies (e.g., ZEB expression measurements in collectively migrating cells) and explains the lack of observed mesenchymalto-hybrid transitions in metastatic cells and in induced pluripotent stem cells. Testable predictions of dynamic gene expression during complete and partial transitions are presented. multistable decision circuit | partial EMT | cancer systems biology | microRNA modeling | metastable intermediate phenotypes U nderstanding cell-fate decisions during embryonic development and tumorigenesis remains a major research challenge in modern developmental and cancer biology (1). Over recent years, we have witnessed rapid progress in mapping the gene regulatory networks associated with cellular phenotype with applications to transitions from epithelial to mesenchymal modalities, to the differentiation of pluripotent stem cells into progenitor cells, to the existence and role of cancer stem-like cells (CSC), and to the production of induced pluripotent stem cells (iPSCs). Cellfate determinations in all of these examples involve changes in expression of various transcription factors (TFs) and microRNAs (miRNAs) that regulate cascades of regulatory networks, ultimately generating genome-wide gene-expression patterns and concomitant protein levels corresponding to a particular cell lineage (fate).The E/M Hybrid Phenotype. An archetypal example of cell-fate decisions concerns the forward and backward transitions between the epithelial (E) and mesenchymal (M) phenotypes (EMT and MET), transitions that play a critical role in embryonic deve...

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Section: Resultssupporting

confidence: 88%

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Jolly

Levine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

495

707

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“…Ras pathway mutation classically activates growth factors including transforming growth factor beta (TGF-b), which induces ZEB1 mRNA, represses Pten mRNA and causes cell proliferation (Supplementary Fig. 6; refs [24][25][26]. Thus, release of growth factors such as TGF-b from K-Ras mutant tumours might be sufficient for ZEB1 induction, PTEN repression and proliferation of tumour-associated fibroblasts.…”

Section: Resultsmentioning

confidence: 99%

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Liu

Huang

et al. 2014

Nat Commun

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Ras pathway mutation is frequent in carcinomas where it induces expression of the transcriptional repressor ZEB1. Although ZEB1 is classically linked to epithelial-mesenchymal transition and tumour metastasis, it has an emerging second role in generation of cancerinitiating cells. Here we show that Ras induction of ZEB1 is required for tumour initiation in a lung cancer model, and we link this function to repression Pten, whose loss is critical for emergence of cancer-initiating cells. These two roles for ZEB1 in tumour progression can be distinguished by their requirement for different levels of ZEB1. A lower threshold of ZEB1 is sufficient for cancer initiation, whereas further induction is necessary for tumour metastasis.

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“…This change of differentiation state, known as epithelial-mesenchymal transition (EMT), 4 has an important role during embryological development, where it enables cell migrations and tissue remodeling, and establishes various cellular lineages in the developing tissues and organs (2). The EMT process is reversible both in embryos and in cancer, and cells cultured in vitro can be switched between epithelial and mesenchymal states by manipulations of EMT-regulating microRNAs and/or transcription factors (3). Reversible EMT-like changes also occur during ES cell differentiation (4) and iPS cell establishment (5)(6)(7), and may also be important in allowing the establishment of cancer metastases (8).…”

Section: Epithelial-mesenchymal Transition (Emt) Is Required For Thementioning

confidence: 99%

Specificity Protein 1 (Sp1) Maintains Basal Epithelial Expression of the miR-200 Family

Kolesnikoff

Attema

Roslan

et al. 2014

Journal of Biological Chemistry

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Background: Epithelial-mesenchymal transition (EMT) is a key process in embryonic development and cancer metastasis. Results: Sp1 activates miR-200 transcription in epithelial cells and prevents EMT. Conclusion: miR-200 family members require Sp1 to drive basal expression and maintain an epithelial state. Significance: Defining the mechanisms controlling the epithelial state has implications for understanding early differentiation and for designing interventions to prevent cancer metastasis.

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

Cited by 533 publications

References 60 publications

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

Specificity Protein 1 (Sp1) Maintains Basal Epithelial Expression of the miR-200 Family

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