Expression of COX-2, mPGE-synthase1, MDR-1 (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 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.
Department of Clinical and Experimental Medicine, Gastroenterology Unit, University 'Federico II', Naples, Italy. nardone@unina.it
Gerardo
G
Nardone
Alba
A
Rocco
Dino
D
Vaira
Stefania
S
Staibano
Alfredo
A
Budillon
Fabiana
F
Tatangelo
Maria G
MG
Sciulli
Federico
F
Perna
Gaetano
G
Salvatore
Maria
M
Di Benedetto
Gaetano
G
De Rosa
Paola
P
Patrignani
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D051546:Cyclooxygenase 2; D004789:Enzyme Activation; D005260:Female; D005756:Gastritis / Q000188:drug therapy / Q000378:metabolism; D016481:Helicobacter Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000032:analysis*; D007527:Isoenzymes / Q000032:analysis*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000382:microbiology; D051020:bcl-X Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C494811:BCL2L1 protein, human; D007527:Isoenzymes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases