Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Title, Alexandra; Hong, Sue-Jean; Pires, Nuno; Hasenöhrl, Lynn; Godbersen, Svenja; Stokar-Regenscheit, Nadine; Bartel, David; Stoffel, Markus
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 14
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07130-z
• Languages: English
• ISSNs: 2041-1723

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 theRip-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 endogenousZeb1 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 ofZeb1 and EMT. Our results thus show that disrupting the in vivo regulation ofZeb1 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. In vivo studies on the regulation of the epithelial-mesenchymal transition (EMT) within a physiological context are lacking. Here it is shown that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, EMT and tumor invasion, and that disruption of Zeb1 regulation by miR-200c is sufficient to drive EMT.