Show simple item record

dc.contributor.authorDuggan, Shane P
dc.contributor.authorBehan, Fiona M
dc.contributor.authorKirca, Murat
dc.contributor.authorZaheer, Abdul
dc.contributor.authorMcGarrigle, Sarah A
dc.contributor.authorReynolds, John V
dc.contributor.authorVaz, Gisela M F
dc.contributor.authorSenge, Mathias O
dc.contributor.authorKelleher, Dermot
dc.date.accessioned2018-11-16T17:02:45Z
dc.date.available2018-11-16T17:02:45Z
dc.date.issued2016-09-02
dc.identifier.citationDuggan, 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.issn2045-2322
dc.identifier.pmid27586588
dc.identifier.pmid27586588
dc.identifier.doi10.1038/srep32638
dc.identifier.urihttp://hdl.handle.net/10147/623919
dc.description.abstractBarrett'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.isoenen_US
dc.publisherNature Publishing Groupen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subjectOESOPHAGEAL CANCERen_US
dc.subjectGENETICSen_US
dc.subject.otherINTESTINAL DISORDERen_US
dc.titleThe 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.typeArticleen_US
dc.contributor.department1 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.journalScientific Reportsen_US
dc.description.fundingNo fundingen_US
dc.description.provinceLeinsteren_US
dc.description.peer-reviewpeer-reviewen_US
dc.source.journaltitleScientific reports
refterms.dateFOA2018-11-16T17:02:45Z


Files in this item

Thumbnail
Name:
srep32638.pdf
Size:
2.889Mb
Format:
PDF
Description:
OA Article

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivs 3.0 United States
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 United States