Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse.
OBJECTIVE
The role of the inducible isoform of nitric oxide synthase (Nos2 or iNOS) in intestinal tumorigenesis is unclear. Conflicting data also exist regarding the ability of Nos2 to modulate expression and/or activity of cyclooxygenase 2 (Cox-2), which promotes intestinal tumorigenesis. Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox-2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis.


METHODS
Apc(Min/+)Nos2(-/-) mice were generated by successive crosses between C57BL/6-Apc(Min/+) and C57BL/6-Nos2(tm1Lau) mice. Adenoma characteristics of age-matched Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice were compared. The level and cellular localization of Nos2 messenger RNA (mRNA) expression in Apc(Min/+)Nos2(+/+) mouse intestine was determined. Cox-2 expression and activity were measured in both intestinal tissue and bone marrow-derived macrophages in vitro.


RESULTS
Apc(Min/+)Nos2(-/-) mice developed significantly more intestinal adenomas than Apc(Min/+)Nos2(+/+) littermates. Epithelial cell Nos2 mRNA expression was decreased in adenomas compared with histologically normal Apc(Min/+)Nos2(+/+) intestine. There was no significant difference in Cox-2 expression or activity in either intestine or bone marrow-derived macrophages from Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) animals.


CONCLUSIONS
Nos2 plays an antineoplastic role in the Apc(Min/+) mouse model of familial adenomatous polyposis. Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse.
Scott
D J
DJ
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, England, UK.
Hull
M A
MA
Cartwright
E J
EJ
Lam
W K
WK
Tisbury
A
A
Poulsom
R
R
Markham
A F
AF
Bonifer
C
C
Coletta
P L
PL
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000201:enzymology; D051546:Cyclooxygenase 2; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D017403:In Situ Hybridization; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000235:genetics*; D007421:Intestine, Small / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D017931:DNA Primers; D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases