Expression of COX-2, mPGE-synthase1, MDR-I (P-gp), and Bcl-XL:: a molecular pathway of H pylori-related gastric carcinogenesis

Helicobacter pylori up-regulates cyclo-oxygenase-2 (COX-2) expression, which in turn is involved in tumourigenesis. Recently, a causal link between COX-2 and multidrug resistance 1 (MDR-1) gene expression, implicated in cancer chemoresistance, has been demonstrated. Thus, the expression of COX-2 and the downstream enzyme involved in PGE(2) biosynthesis, microsomal PGE-synthase(1) (mPGES(1)), was correlated with P-gp, the product of MDR-1, and the anti-apoptotic protein, Bcl-x(L), in gastric biopsies from patients with H pylori infection and in patients with gastric cancer. In a retrospective analysis of endoscopic and pathology files, 40 H pylori-negative patients (Hp -), 50 H pylori-positive patients who responded to eradication therapy (Hp+R), 84 H pylori-positive patients who did not respond to eradication therapy (Hp+NR), and 30 patients with gastric cancer (18 intestinal and 12 diffuse types) were selected. COX-2, mPGES(1), P-gp, and Bcl-x(L) were detected by immunohistochemistry. COX-2, mPGES(1), P-gp, and Bcl-x(L) expression was undetectable in gastric mucosa from Hp- patients. By contrast, COX-2 and mPGES(1) expression was detected in 42% and 44% of Hp+R patients, respectively, and in up to 66% (range 63-66%) of Hp+NR patients (p < 0.05). The expression of COX-2 and mPGES(1) correlated significantly (p < 0.0001) with that of P-gp and Bcl-x(L). High levels of COX-2, mPGES(1), P-gp, and Bcl-x(L), expression were found in intestinal-type gastric cancer samples. In conclusion, H pylori-dependent induction of COX-2 and mPGES(1) is associated with enhanced production of P-gp and Bcl-x(L) that may contribute to gastric tumourigenesis and resistance to therapy. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.