title: The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival.
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.
authors: Department of Medicine, Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada.|Life Science Institute, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors: Shane P
authors: SP
authors: Duggan
authors: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin, Ireland.
authors: Fiona M
authors: FM
authors: Behan
authors: Department of Gastroenterology, St James' Hospital, Dublin, Ireland.
authors: Murat
authors: M
authors: Kirca
authors: Department of Gastroenterology, St James' Hospital, Dublin, Ireland.
authors: Abdul
authors: A
authors: Zaheer
authors: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin 8, Ireland.
authors: Sarah A
authors: SA
authors: McGarrigle
authors: Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin 8, Ireland.
authors: John V
authors: JV
authors: Reynolds
authors: Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity College Dublin, the University of Dublin, St James' Hospital, Dublin 8, Ireland.
authors: Gisela M F
authors: GM
authors: Vaz
authors: Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity College Dublin, the University of Dublin, St James' Hospital, Dublin 8, Ireland.
authors: Mathias O
authors: MO
authors: Senge
authors: Department of Medicine, Division of Gastroenterology, University of British Columbia, 2775 Laurel Street, Vancouver, British Columbia, Canada.|Life Science Institute, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada.
authors: Dermot
authors: D
authors: Kelleher
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D017209:Apoptosis / Q000235:genetics; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D050993:GATA6 Transcription Factor / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D005764:Gastroesophageal Reflux; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D015894:Genome, Human; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015203:Reproducibility of Results; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D050993:GATA6 Transcription Factor; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D051020:bcl-X Protein