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