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


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.

SUBMITTER: Title AC 

PROVIDER: S-EPMC6220299 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Title Alexandra C AC   Hong Sue-Jean SJ   Pires Nuno D ND   Hasenöhrl Lynn L   Godbersen Svenja S   Stokar-Regenscheit Nadine N   Bartel David P DP   Stoffel Markus M  

Nature communications 20181107 1


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. Strik  ...[more]

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