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Carcinogenesis Advance Access published online on November 20, 2006
Carcinogenesis, doi:10.1093/carcin/bgl224
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 13, 2006
Revised November 7, 2006
Accepted November 8, 2006

CARCINOGENESIS

Induction of Inducible Nitric Oxide synthase: A protective Mechanism in Colitis-Induced Adenocarcinoma

Rui Zhang 1, Adrienne Ma 2, Stefan J. Urbanski 3, and Donna-Marie McCafferty 2 *

1 Department of Digest, 2nd Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030001 China; Gastrointestinal Research Group, Dept. of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
2 Gastrointestinal Research Group, Dept. of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
3 Department of Pathology, University of Calgary, Calgary, Alberta, Canada T2N 4N1

* To whom correspondence should be addressed.
Donna-Marie McCafferty, E-mail: dmmccaff{at}ucalgary.ca


  Abstract

A close association between inflammatory bowel disease (IBD) and increased risk of developing adenocarcinoma exisits. Moreover, chronic induction of high levels of nitric oxide (NO) produced from inducible NO synthase (iNOS) is a consistent observation in IBD. In this study we made IL-10-deficient (IL-10-/-) /iNOS-/- double deficient mice and studied the development of adenocarcinoma. Mice > 6 months of age were compared to healthy wild type (WT) controls. Inflammation was assessed using macrocopic/ histological scores and myeloperoxidase activity as an indication of granulocyte infiltration. Mucosal polyps were scored macroscopically and hyperproliferation quantified by BrdU immunohistochemistry. Dysplastic changes were assessed histologically based on cytologic and architectured atypia as well as the presence of submucosal invasion. p53 and {beta}-catenin messenger RNA and protein expression were assessed using real-time PCR and immunohistochemistry respectively. Inflammatory indices were significantly elevated in IL-10-/- over WT and not significantly different from IL-10-/-/iNOS-/- mice. The incidence of mucosal polyps was similar between IL-10-/- (79 %) and IL-10-/-/iNOS-/- mice (83 %) however significantly higher numbers of polyps were observed in the absence of iNOS (p<0.05). Hyperproliferation was noted in both groups. Signs of dysplasia and submucosal invasion were significantly higher in IL-10-/-/iNOS-/- compared with IL-10-/- mice (p<0.05). No significant increase in p53 and {beta}-catenin mRNA levels was observed in IL-10-/- mice over WT however a two-fold (p=0.06) and three-fold (p<0.05) increase respectively was noted in IL-10-/-/iNOS-/- mice. Our data suggest exposure to chronic NO limits abnormal p53 and {beta}-catenin expression and reduces incidence of adenocarcinoma in IL-10-/- mice.

Keywords: colitis, adenocarcinoma; IL-10-deficient mice; iNOS; nitric oxide; p53; {beta}-catenin.
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