The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival.
dc.contributor.author | Duggan, Shane P | |
dc.contributor.author | Behan, Fiona M | |
dc.contributor.author | Kirca, Murat | |
dc.contributor.author | Zaheer, Abdul | |
dc.contributor.author | McGarrigle, Sarah A | |
dc.contributor.author | Reynolds, John V | |
dc.contributor.author | Vaz, Gisela M F | |
dc.contributor.author | Senge, Mathias O | |
dc.contributor.author | Kelleher, Dermot | |
dc.date.accessioned | 2018-11-16T17:02:45Z | |
dc.date.available | 2018-11-16T17:02:45Z | |
dc.date.issued | 2016-09-02 | |
dc.identifier.citation | Duggan, S. P. et al. The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival. Sci. Rep. 6, 32638; doi: 10.1038/srep32638 (2016). | en_US |
dc.identifier.issn | 2045-2322 | |
dc.identifier.pmid | 27586588 | |
dc.identifier.pmid | 27586588 | |
dc.identifier.doi | 10.1038/srep32638 | |
dc.identifier.uri | http://hdl.handle.net/10147/623919 | |
dc.description.abstract | 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. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Nature Publishing Group | en_US |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/us/ | * |
dc.subject | OESOPHAGEAL CANCER | en_US |
dc.subject | GENETICS | en_US |
dc.subject.other | INTESTINAL DISORDER | en_US |
dc.title | The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival. | en_US |
dc.type | Article | en_US |
dc.contributor.department | 1 Department of Medicine, Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada. 2 Life Science Institute, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada. 3 Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin, Ireland. 4 Department of Gastroenterology, St James' Hospital, Dublin, Ireland. 5 Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin 8, Ireland. 6 Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity College Dublin, the University of Dublin, St James' Hospital, Dublin 8, Ireland. | en_US |
dc.identifier.journal | Scientific Reports | en_US |
dc.description.funding | No funding | en_US |
dc.description.province | Leinster | en_US |
dc.description.peer-review | peer-review | en_US |
dc.source.journaltitle | Scientific reports | |
refterms.dateFOA | 2018-11-16T17:02:45Z |