Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion

Alexandra C. Title, Sue-Jean Hong, Nuno D. Pires, Lynn Hasenöhrl, Svenja Godbersen, Nadine Stokar-Regenscheit, David P. Bartel and Markus Stoffel ()
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Alexandra C. Title: ETH Zurich
Sue-Jean Hong: Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research
Nuno D. Pires: ETH Zurich
Lynn Hasenöhrl: ETH Zurich
Svenja Godbersen: ETH Zurich
Nadine Stokar-Regenscheit: University of Bern
David P. Bartel: Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research
Markus Stoffel: ETH Zurich

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07130-z

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