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Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion
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 cont...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220299/ https://www.ncbi.nlm.nih.gov/pubmed/30405106 http://dx.doi.org/10.1038/s41467-018-07130-z |
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author | Title, Alexandra C. Hong, Sue-Jean Pires, Nuno D. Hasenöhrl, Lynn Godbersen, Svenja Stokar-Regenscheit, Nadine Bartel, David P. Stoffel, Markus |
author_facet | Title, Alexandra C. Hong, Sue-Jean Pires, Nuno D. Hasenöhrl, Lynn Godbersen, Svenja Stokar-Regenscheit, Nadine Bartel, David P. Stoffel, Markus |
author_sort | Title, Alexandra C. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6220299 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62202992018-11-08 Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion Title, Alexandra C. Hong, Sue-Jean Pires, Nuno D. Hasenöhrl, Lynn Godbersen, Svenja Stokar-Regenscheit, Nadine Bartel, David P. Stoffel, Markus Nat Commun Article 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. Nature Publishing Group UK 2018-11-07 /pmc/articles/PMC6220299/ /pubmed/30405106 http://dx.doi.org/10.1038/s41467-018-07130-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Title, Alexandra C. Hong, Sue-Jean Pires, Nuno D. Hasenöhrl, Lynn Godbersen, Svenja Stokar-Regenscheit, Nadine Bartel, David P. Stoffel, Markus Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title | Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title_full | Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title_fullStr | Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title_full_unstemmed | Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title_short | Genetic dissection of the miR-200–Zeb1 axis reveals its importance in tumor differentiation and invasion |
title_sort | genetic dissection of the mir-200–zeb1 axis reveals its importance in tumor differentiation and invasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220299/ https://www.ncbi.nlm.nih.gov/pubmed/30405106 http://dx.doi.org/10.1038/s41467-018-07130-z |
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