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I Beales, Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR4 7UZ, United Kingdom
O Ogunwobi, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom

Correspondence: Ian Beales, Email: i.beales{at}uea.ac.uk

Abstract

Barrett’s oesophagus and oesophageal adenocarcinoma are regarded as complications of gastro-oesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for oesophageal adenocarcinoma cells. We have examined the effects of glycine-extended gastrin, an alternative product of progastrin processing on apoptosis in the QhERT Barrett’s oesophageal cell line and OE33 and BIC-1 oesophageal adenocarcinoma cells. G-Gly inhibited serum-starvation and camptothecin-induced apoptosis in all 3 cell lines, G17 was only effective in OE33 cells. In contrast to the effects of G-17, the anti-apoptotic effect of G-Gly was independent of both the CCK2 receptor and COX-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependant STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL-XL but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL-XL in OE33 cells.

We conclude that glycine-extended gastrin inhibits apoptosis in Barrett’s oesophagus and oesophageal adenocarcinoma via mechanisms distinct from those activated by G17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in Barrett’s oesophagus.