Expression of COX‐2, mPGE‐synthase₁, MDR‐1 (P‐gp), and Bcl‐x_L: a molecular pathway of H pylori‐related gastric carcinogenesis

Abstract

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 PGE2 biosynthesis, microsomal PGE-synthase1 (mPGES1), was correlated with P-gp, the product of MDR-1, and the anti-apoptotic protein, Bcl-xL, 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, mPGES1, P-gp, and Bcl-xL were detected by immunohistochemistry. COX-2, mPGES1, P-gp, and Bcl-xL expression was undetectable in gastric mucosa from Hp- patients. By contrast, COX-2 and mPGES1 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 mPGES1 correlated significantly (p < 0.0001) with that of P-gp and Bcl-xL. High levels of COX-2, mPGES1, P-gp, and Bcl-xL expression were found in intestinal-type gastric cancer samples. In conclusion, H pylori-dependent induction of COX-2 and mPGES1 is associated with enhanced production of P-gp and Bcl-xL that may contribute to gastric tumourigenesis and resistance to therapy.

Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target

“…It has been proposed that TNF-␣-dependent inflammation is responsible for the gastric hyperplasia in the transgenic mouse model (Oshima et al, 2005). Helicobacter pylori-dependent induction of COX-2 and mPGES-1 is associated with enhanced production of P-gp (product of multidrug resistance-1) and Bcl-X L (the antiapoptic protein) that 218 may contribute to gastric tumorigenesis and resistance to therapy (Nardone et al, 2004). Transgenic mice simultaneously expressing COX-2 and mPGES-1 in gastric epithelial cells developed metaplasia, hyperplasia, and tumorous growths in the glandular stomach.…”

Mechanism of P-glycoprotein Expression in the SGC7901 Human Gastric Adenocarcinoma Cell Line Induced by Cyclooxygenase-2

“…A large number of studies show that COX-2 participates in the regulation and control of multidrug resistance, and there exists correlation between the expression of COX-2 and P-gp expression (Nardone et al, 2004;Miller et al, 2006;Liu et al, 2009) in many types of tumors. It is not clear how COX-2 stimulates the expression of P-gp.…”

Short-term Celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model

“…is associated with enhanced production of multidrug resistance-1 (MDR-1) and Bcl-xL proteins that may contribute to gastric tumorigenesis and resistance to therapy [13] . Therefore, it is important to find an alternative chemoprevention for these patients.…”