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

Author

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  • Alexandra C. Title

    (ETH Zurich
    ETH Zurich)

  • Sue-Jean Hong

    (Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research
    Massachusetts Institute of Technology)

  • 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
    Massachusetts Institute of Technology)

  • Markus Stoffel

    (ETH Zurich
    ETH Zurich
    University of Zurich)

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.

Suggested Citation

  • Alexandra C. Title & Sue-Jean Hong & Nuno D. Pires & Lynn Hasenöhrl & Svenja Godbersen & Nadine Stokar-Regenscheit & David P. Bartel & Markus Stoffel, 2018. "Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07130-z
    DOI: 10.1038/s41467-018-07130-z
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    Cited by:

    1. Mary P. LaPierre & Katherine Lawler & Svenja Godbersen & I. Sadaf Farooqi & Markus Stoffel, 2022. "MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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