The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival

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2016Access:
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Duggan S.P, Behan F.M, Kirca M, Zaheer A, McGarrigle S.A, Reynolds J.V, Vaz G.M.F, Senge M.O, Kelleher D, The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival, Scientific Reports, 6, 2016, 32638 -Download Item:
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 metaprofile
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 overexpression
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.
Sponsor
Grant Number
Health Research Board (HRB)
HRB-TRA.2007.11
Author's Homepage:
http://people.tcd.ie/sengemhttp://people.tcd.ie/reynoljv
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PUBLISHEDExport Date: 8 December 2016
Author: SENGE, MATHIAS; REYNOLDS, JOHN
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Scientific Reports6
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Barrett’s oesophagusDOI:
http://dx.doi.org/10.1038/srep32638Metadata
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