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Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition

Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and w...

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Autores principales: Quaresma, Margarida C., Pankonien, Ines, Clarke, Luka A., Sousa, Luís S., Silva, Iris A. L., Railean, Violeta, Doušová, Tereza, Fuxe, Jonas, Amaral, Margarida D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588414/
https://www.ncbi.nlm.nih.gov/pubmed/33106471
http://dx.doi.org/10.1038/s41419-020-03119-z
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author Quaresma, Margarida C.
Pankonien, Ines
Clarke, Luka A.
Sousa, Luís S.
Silva, Iris A. L.
Railean, Violeta
Doušová, Tereza
Fuxe, Jonas
Amaral, Margarida D.
author_facet Quaresma, Margarida C.
Pankonien, Ines
Clarke, Luka A.
Sousa, Luís S.
Silva, Iris A. L.
Railean, Violeta
Doušová, Tereza
Fuxe, Jonas
Amaral, Margarida D.
author_sort Quaresma, Margarida C.
collection PubMed
description Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial–mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.
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spelling pubmed-75884142020-10-29 Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition Quaresma, Margarida C. Pankonien, Ines Clarke, Luka A. Sousa, Luís S. Silva, Iris A. L. Railean, Violeta Doušová, Tereza Fuxe, Jonas Amaral, Margarida D. Cell Death Dis Article Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial–mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein. Nature Publishing Group UK 2020-10-26 /pmc/articles/PMC7588414/ /pubmed/33106471 http://dx.doi.org/10.1038/s41419-020-03119-z Text en © The Author(s) 2020 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
Quaresma, Margarida C.
Pankonien, Ines
Clarke, Luka A.
Sousa, Luís S.
Silva, Iris A. L.
Railean, Violeta
Doušová, Tereza
Fuxe, Jonas
Amaral, Margarida D.
Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title_full Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title_fullStr Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title_full_unstemmed Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title_short Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition
title_sort mutant cftr drives twist1 mediated epithelial–mesenchymal transition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588414/
https://www.ncbi.nlm.nih.gov/pubmed/33106471
http://dx.doi.org/10.1038/s41419-020-03119-z
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