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The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs

Abstract

Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1–miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.

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Figure 1: ZEB1 in pancreatic cancer progression.
Figure 2: ZEB1 is crucial for properties attributed to cancer stem cells.
Figure 3: ZEB1 targets stemness-inhibiting miRNAs.
Figure 4: miRNAs and ZEB1 control stem cell properties.
Figure 5: Validation in mouse and human primary tumour cells.

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Acknowledgements

We thank J. Pfannstiel, K. Meyer, M. Berthold, S. Hempel and A. Schmitt for expert technical assistance. This work was supported by grants to T.B. from the EU MCSC contract no. 037297, the DFG (no. BR 1399/4-3 and BR 1399/5-1) and the Deutsche Krebshilfe (no. 106958), and to V.G.B. from Cancer Research UK (C157/A9148).

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Authors

Contributions

U.W. and F.Z. performed animal and Gemza selection experiments and analysed data. J.S, U.C.B., O.S, A.S. and B.W. performed stem cell and miRNA assays and analysed data. C.V. and M.P.S. performed ES cell analyses. D.D. and A.z.H. were responsible for collection and analyses of human tumours using in situ methods. V.G.B., J.M. and O.S. isolated and performed experiments with mouse pancreatic cancer cells. J.S. isolated and performed experiments with human pancreatic cancer cells. C.H., U.H. and T.K. collected and analysed clinical samples and follow-up data. S.B. performed stem cell assays, analysed data and was involved in project planning. T.B. planned and coordinated the project, analysed data and wrote the manuscript.

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Correspondence to Thomas Brabletz.

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Wellner, U., Schubert, J., Burk, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11, 1487–1495 (2009). https://doi.org/10.1038/ncb1998

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