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The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival
Barrett’s oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009315/ https://www.ncbi.nlm.nih.gov/pubmed/27586588 http://dx.doi.org/10.1038/srep32638 |
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author | Duggan, Shane P. Behan, Fiona M. Kirca, Murat Zaheer, Abdul McGarrigle, Sarah A. Reynolds, John V. Vaz, Gisela M. F. Senge, Mathias O. Kelleher, Dermot |
author_facet | Duggan, Shane P. Behan, Fiona M. Kirca, Murat Zaheer, Abdul McGarrigle, Sarah A. Reynolds, John V. Vaz, Gisela M. F. Senge, Mathias O. Kelleher, Dermot |
author_sort | Duggan, Shane P. |
collection | PubMed |
description | Barrett’s oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defined. Consequently, the contribution of intestine-enriched factors expressed within BO to oncogenesis is unclear. Herein, using transcriptomics we define the intestine-enriched genes expressed in meta-profiles of BO and OAC. Interestingly, 77% of the genes differentially expressed in a meta-profile of BO were similarly expressed in intestinal tissues. Furthermore, 85% of this intestine-like signature was maintained upon transition to OAC. Gene networking analysis of transcription factors within this signature revealed a network centred upon NR5A2, GATA6 and FOXA2, whose over-expression was determined in a cohort of BO and OAC patients. Simulated acid reflux was observed to induce the expression of both NR5A2 and GATA6. Using siRNA-mediated silencing and an NR5A2 antagonist we demonstrate that NR5A2-mediated cancer cell survival is facilitated through augmentation of GATA6 and anti-apoptotic factor BCL-XL levels. Abrogation of NR5A2-GATA6 expression in conjunction with BCL-XL co-silencing resulted in synergistically increased sensitivity to chemotherapeutics and photo-dynamic therapeutics. These findings characterize the intestine-like signature associated with IM which may have important consequences to adenocarcinogenesis. |
format | Online Article Text |
id | pubmed-5009315 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50093152016-09-08 The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival Duggan, Shane P. Behan, Fiona M. Kirca, Murat Zaheer, Abdul McGarrigle, Sarah A. Reynolds, John V. Vaz, Gisela M. F. Senge, Mathias O. Kelleher, Dermot Sci Rep Article Barrett’s oesophagus (BO), an intestinal-type metaplasia (IM), typically arising in conjunction with gastro-oesophageal reflux disease, is a prominent risk factor for the development of oesophageal adenocarcinoma (OAC). The molecular similarities between IM and normal intestinal tissues are ill-defined. Consequently, the contribution of intestine-enriched factors expressed within BO to oncogenesis is unclear. Herein, using transcriptomics we define the intestine-enriched genes expressed in meta-profiles of BO and OAC. Interestingly, 77% of the genes differentially expressed in a meta-profile of BO were similarly expressed in intestinal tissues. Furthermore, 85% of this intestine-like signature was maintained upon transition to OAC. Gene networking analysis of transcription factors within this signature revealed a network centred upon NR5A2, GATA6 and FOXA2, whose over-expression was determined in a cohort of BO and OAC patients. Simulated acid reflux was observed to induce the expression of both NR5A2 and GATA6. Using siRNA-mediated silencing and an NR5A2 antagonist we demonstrate that NR5A2-mediated cancer cell survival is facilitated through augmentation of GATA6 and anti-apoptotic factor BCL-XL levels. Abrogation of NR5A2-GATA6 expression in conjunction with BCL-XL co-silencing resulted in synergistically increased sensitivity to chemotherapeutics and photo-dynamic therapeutics. These findings characterize the intestine-like signature associated with IM which may have important consequences to adenocarcinogenesis. Nature Publishing Group 2016-09-02 /pmc/articles/PMC5009315/ /pubmed/27586588 http://dx.doi.org/10.1038/srep32638 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Duggan, Shane P. Behan, Fiona M. Kirca, Murat Zaheer, Abdul McGarrigle, Sarah A. Reynolds, John V. Vaz, Gisela M. F. Senge, Mathias O. Kelleher, Dermot The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title | The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title_full | The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title_fullStr | The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title_full_unstemmed | The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title_short | The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival |
title_sort | characterization of an intestine-like genomic signature maintained during barrett’s-associated adenocarcinogenesis reveals an nr5a2-mediated promotion of cancer cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009315/ https://www.ncbi.nlm.nih.gov/pubmed/27586588 http://dx.doi.org/10.1038/srep32638 |
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