• 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; 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. (Nature Publishing Group, 2016-09-02)
      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.