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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.

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
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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
Advisors
Editors
Other Contributors
Departments
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.
Date
2016-09-02
Date Submitted
Keywords
OESOPHAGEAL CANCER
GENETICS
Other Subjects
INTESTINAL DISORDER
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Start Date
Collaborators
Principal Investigators
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Alternative Titles
Publisher
Nature Publishing Group
URI
https://hdl.handle.net/10147/623919
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.
Language
en
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).
ISSN
2045-2322
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ISBN
DOI
10.1038/srep32638
PMID
27586588
27586588
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