Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion
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Title, Alexandra C.; Pires, Nuno D.; Hasenöhrl, Lynn; Godbersen, Svenja; Stokar-Regenscheit, Nadine; Stoffel, Markus; Hong, Sue-Jean; Bartel, David; ... Show more Show less
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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.
Date issued
2018-11Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical ResearchJournal
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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ISSN
2041-1723