Decreased Helicobacter pylori associated gastric carcinogenesis in mice lacking inducible nitric oxide synthase.
OBJECTIVE
Overproduction of nitric oxide via inducible nitric oxide synthase (iNOS) is suggested to be a significant pathogenic factor in Helicobacter pylori induced gastritis. The purpose of this study was to examine the role of iNOS in H pylori associated gastric carcinogenesis.


METHODS
Two types of mice were used in this study: iNOS deficient mice (iNOS-/-) and wild-type littermates. Gastric cancer was generated in mice using a combination treatment comprising N-methyl-N-nitrosourea administration and H pylori infection. Fifty weeks after treatment, tumours in gastric tissues from both types of mice were examined using histopathology, immunohistochemistry, and immunoblotting for iNOS and 3-nitrotyrosine.


RESULTS
The overall incidence of gastric cancer at week 50 was significantly lower in iNOS-/- compared with iNOS wild-type mice (p<0.05). When analysed according to tumour pathology, the incidence of gastric adenocarcinoma was significantly lower in iNOS-/- compared with iNOS wild-type mice (p<0.05). Immunostaining for iNOS was clearly observed in adenocarcinoma cells of iNOS wild-type mice, and was characterised by a strong cytoplasmic expression pattern. 3-Nitrotyrosine was expressed mostly in the area of the lamina propria of gastritis and adenoma lesions in iNOS wild-type mice. Immunoblotting analyses showed that iNOS and 3-nitrotyrosine were also expressed in both adenoma and adenocarcinoma tissues from iNOS wild-type mice. iNOS and 3-nitrotyrosine expression was greater in tumour tissues than in non-tumour tissues.


CONCLUSIONS
These findings suggest that iNOS contributes to H pylori associated gastric carcinogenesis in mice.
Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, San 56-1, Shillim-dong, Kwanak-gu, Seoul 151-742, Korea.
K T
KT
Nam
S-Y
SY
Oh
B
B
Ahn
Y B
YB
Kim
D D
DD
Jang
K-H
KH
Yang
K-B
KB
Hahm
D-Y
DY
Kim
D000230:Adenocarcinoma / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D000236:Adenoma / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D005756:Gastritis / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori / Q000254:growth & development; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D013270:Stomach / Q000382:microbiology; D013274:Stomach Neoplasms / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse