Increased oxidative DNA damage, inducible nitric oxide synthase, nuclear factor kappaB expression and enhanced antiapoptosis-related proteins in Helicobacter pylori-infected non-cardiac gastric adenocarcinoma.
OBJECTIVE
Several epidemiological studies have demonstrated a close association between Helicobacter pylori (H pylori) infection and non-cardiac carcinoma of the stomach. H pylori infection induces active inflammation with neutrophilic infiltrations as well as production of oxygen free radicals that can cause DNA damage. The DNA damage induced by oxygen free radicals could have very harmful consequences, leading to gene modifications that are potentially mutagenic and/or carcinogenic. The aims of the present study were to assess the effect of H pylori infection on the expression of inducible nitric oxidative synthase (iNOS) and the production of 8-hydroxy-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA injury in human gastric mucosa with and without tumor lesions, and to assess the possible factors affecting cell death signaling due to oxidative DNA damage.


METHODS
In this study, 40 gastric carcinoma specimens and adjacent specimens were obtained from surgical resection. We determined the level of 8-OHdG formation by HPLC-ECD, and the expression of iNOS and mechanism of cell death signaling (including nuclear factor-kappaB(NFkappaB), MEKK-1, Caspase 3, B Cell lymphomal leukemia-2 (Bcl-2), inhibitor of apoptosis protein (IAP) and myeloid cell leukemia-1 (Mcl-1)) by Western-blot assay.


RESULTS
The concentrations of 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP were significantly higher in cancer tissues than in adjacent non-cancer tissues. In addition, significantly higher concentrations of 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP were detected in patients infected with H pylori compared with patients who were not infected with H pylori. Furthermore, 8-OHdG, iNOS, NFkappaB, Mcl-1 and IAP concentrations were significantly higher in stage 3 and 4 patients than in stage 1 and 2 patients.


CONCLUSIONS
Chronic H pylori infection induces iNOS expression and subsequent DNA damage as well as enhances anti-apoptosis signal transduction. This sequence of events supports the hypothesis that oxygen-free radical-mediated damage due to H pylori plays a pivotal role in the development of gastric carcinoma in patients with chronic gastritis.
Chang
Chi-Sen
CS
Institute of Biochemistry, College of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo North Road, 402 Taichung, Taiwan, China.
Chen
Wei-Na
WN
Lin
Hui-Hsuan
HH
Wu
Cheng-Chung
CC
Wang
Chau-Jong
CJ
D000230:Adenocarcinoma / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D004249:DNA Damage; D005260:Female; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D016480:Helicobacter pylori; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000150:complications / Q000235:genetics* / Q000503:physiopathology
D016328:NF-kappa B; D011506:Proteins; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II