Zeb1 Regulates E-cadherin and Epcam (Epithelial Cell Adhesion Molecule) Expression to Control Cell Behavior in Early Zebrafish Development

Vannier, Corinne; Mock, Kerstin; Brabletz, Thomas; Driever, Wolfgang

doi:10.1074/jbc.m113.467787

Cited by 71 publications

(61 citation statements)

References 64 publications

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“…Our (1/2,1/2) state hypothesis is consistent with recent studies of gastrulation in Drosophila embryos that show that collectively migrating cells, which correspond to the hybrid state, coexpress ZEB1 and E-cadherin (39). The latter is inhibited by ZEB and SNAIL (Fig.…”

Section: Discussionsupporting

confidence: 92%

“…We propose that experiments should be carried out involving collective cell migration similar to those reported in ref. 39, in which the levels of both miR-200 and ZEB would be directly measured (instead of focusing exclusively on downstream effectors such as E-cadherin and vimentin). Furthermore, according to our analysis, the (1/2, 1/2) state, and thus the hybrid phenotype, can exist only if ZEB is selfactivating.…”

Section: Resultsmentioning

confidence: 99%

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

Jolly

Levine

et al. 2013

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

478

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: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

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

Jolly

Levine

et al. 2013

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

478

707

View full text Add to dashboard Cite

show abstract

“…A comparable beneficial effect of Epcam on invasion and migration was observed in Xenopus (11,13) and human breast cancer cell lines (14,15). In contrast, loss of Epcam during epithelial-to-mesenchymal transition (EMT) in circulating and disseminating tumor cells (16 -18) and in zebrafish was reported (19). Knockdown of EPCAM in esophageal carcinoma cells induced a mesenchymal phenotype along with increased migration and invasion (16) and conformed with a dynamic expression of EPCAM during tumor progression (20).…”

mentioning

confidence: 77%

Cleavage and Cell Adhesion Properties of Human Epithelial Cell Adhesion Molecule (HEPCAM)

Tsaktanis¹,

Kremling²,

Pavšič

et al. 2015

Journal of Biological Chemistry

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Background: EPCAM was described as a cell adhesion molecule involved in regulation of proliferation through regulated intramembrane proteolysis. Results: Proteolysis was characterized in-depth, but cleavage or knock-out of HEPCAM did not affect adhesion. Conclusion: Direct adhesion through HEPCAM is questionable. Significance: Unraveling cleavage sites of EPCAM is crucial for developing inhibitors; however, its cell adhesion function may reveal context dependence.

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“…Interestingly, Zeb1 (a known transcription factor inducing EMT) represses both E-cadherin and EpCAM by binding to the EpCAM promoter [133], yet the expression of E-cadherin and EpCAM is related to a stem cell-like phenotype [134,135]; in basal-like breast cancer, EpCAM and P-cadherin both appear to be associated with the CSC phenotype [108]. As described for the hallmarks of cancer [33], the timing and ordering of these events appears to differ between normal and tumourous tissues, between different tissue and tumour types, and most likely within the same tumour.…”

Section: Cadherins and Epcammentioning

confidence: 99%

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

Bryan

2015

Phil. Trans. R. Soc. B

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Cadherins are mediators of cell-cell adhesion in epithelial tissues. E-cadherin is a known tumour suppressor and plays a central role in suppressing the invasive phenotype of cancer cells. However, the abnormal expression of N-and P-cadherin ('cadherin switching', CS) has been shown to promote a more invasive and m alignant phenotype of cancer, with P-cadherin possibly acting as a key mediator of invasion and metastasis in bladder cancer. Cadherins are also implicated in numerous signalling events related to embryonic development, tissue morphogenesis and homeostasis. It is these wide ranging effects and the serious implications of CS that make the cadherin cell adhesion molecules and their related pathways strong candidate targets for the inhibition of cancer progression, including bladder cancer. This review focuses on CS in the context of bladder cancer and in particular the switch to P-cadherin expression, and discusses other related molecules and phenomena, including EpCAM and the development of the cancer stem cell phenotype.

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Zeb1 Regulates E-cadherin and Epcam (Epithelial Cell Adhesion Molecule) Expression to Control Cell Behavior in Early Zebrafish Development

Cited by 71 publications

References 64 publications

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

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

Cleavage and Cell Adhesion Properties of Human Epithelial Cell Adhesion Molecule (HEPCAM)

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

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