Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion
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Author(s)
Title, Alexandra C.
Pires, Nuno D.
Hasenöhrl, Lynn
Godbersen, Svenja
Stokar-Regenscheit, Nadine
Stoffel, Markus
Hong, Sue-Jean
Bartel, David
Date Issued
November 2018
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Title, Alexandra C., Sue-Jean Hong, Nuno D. Pires, Lynn Hasenöhrl, Svenja Godbersen, Nadine Stokar-Regenscheit, David P. Bartel, and Markus Stoffel. “Genetic Dissection of the miR-200–Zeb1 Axis Reveals Its Importance in Tumor Differentiation and Invasion.” Nature Communications 9, no. 1 (November 7, 2018). © 2018 The Authors
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Final published version
Abstract
The epithelial-to-mesenchymal transition (EMT) is an important mechanism for cancer progression and metastasis. Numerous in vitro and tumor-profiling studies point to the miR-200–Zeb1 axis as crucial in regulating this process, yet in vivo studies involving its regulation within a physiological context are lacking. Here, we show that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, initiates an EMT expression program, and promotes tumor invasion. Strikingly, disrupting the miR-200 sites of the endogenous Zeb1 locus causes a similar phenotype. Reexpressing members of the miR-200 superfamily in vitro reveals that the miR-200c family and not the co-expressed and closely related miR-141 family is responsible for regulation of Zeb1 and EMT. Our results thus show that disrupting the in vivo regulation of Zeb1 by miR-200c is sufficient to drive EMT, thus highlighting the importance of this axis in tumor progression and invasion and its potential as a therapeutic target.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-018-07130-z
