Gastrin induces cyclooxygenase (COX)-2 expression in Barrett’s esophagus

S Abdalla^a,b, PS Sirieix^a, IR Sanderson^b, RC Fitzgerald^a

^aCancer Cell Unit, MRC/Hutchison Building, Cambridge, United Kingdom, ^bThe Adult and Paediatric Gastroenterology Department, Barts and The London School of Medicine and Dentistry, London, United Kingdom

COX-2 enzyme is induced in inflammation and cancer and is expressed in Barrett’s epithelium (BE) and associated adenocarcinoma (AC). However, there are no previous longitudinal studies that examined COX-2 expression in the progression of BE to cancer. Furthermore, the possible role of gastrin in inducing COX-2 has not been analysed, although most BE patients use proton pump inhibitors that may cause moderate hypergastrinemia. This study was designed to investigate the role of COX-2 in BE and the associated AC and its relationship to gastrin. Methods Immunohistochemistry was utilised to examine COX-2 expression in 27 BE patients (9 progressed to AC and 18 did not) followed yearly for a mean of 4.8 years. Semi-quantitative RT-PCR was used to determine gastrin and its CCK-2 receptor mRNA in the following samples (n=30): esophageal squamous epithelium (NE), BE, AC and duodenal biopsies (DU), and in squamous (OE21) and BE cell lines (SEG-1, BIC-1 and OE33). Western blotting was used to determine COX-2 expression in NE and BE biopsies following gastrin stimulation in organ culture and in Barrett’s cell lines. Results There was no difference between COX-2 expression in BE regardless of whether patients progressed to AC. However, both patient groups expressed more COX-2 over time during the follow up period (P<0.005). All NE, BE, DU and AC biopsies expressed endogenous gastrin mRNA. CCK-2 receptor is expressed in 75% NE, 80% BE, 60% dysplastic BE, 50% AC and 100% DU biopsies used. Gastrin (G-17) induced COX-2 expression in NE, BE and DU explants suggesting a possible role for gastrin in COX-2 induction and BE progression. All Barrett’s cell lines expressed variable amounts of gastrin and CCK-2 mRNA, and gastrin induced COX-2 in SEG-1 cells. Conclusion COX-2 expression occurs early in BE and increases over time. Epithelial cells may synthesize their own gastrin that could have a potential role in inducing COX-2 in BE and AC.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 897 (Precursor lesions).