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Carcinogenesis Advance Access originally published online on July 7, 2008
Carcinogenesis 2008 29(8):1648-1654; doi:10.1093/carcin/bgn156
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transgenic cyclooxygenase-2 expression and high salt enhanced susceptibility to chemical-induced gastric cancer development in mice

Wai K. Leung1,*, Kai-chun Wu3, Christine Y. P. Wong1, Alfred S. L. Cheng1, Arthur K. K. Ching2, Anthony W. H. Chan1, Wilson W. S. Chong1, Minnie Y. Y. Go1, Jun Yu1, Ka-Fai To1, Xin Wang3, Y. L. Chui2, D. M. Fan3 and Joseph J. Y. Sung1

1 Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences
2 Clinical Immunology Unit, The Chinese University of Hong Kong, Hong Kong, China
3 Institute of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China

* To whom correspondence should be addressed. Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. Tel: +852 2632 3173; Fax: +852 2637 3852; Email: dr_wkleung{at}alumni.cuhk.net

Cyclooxoygenase (COX)-2 overexpression is involved in gastric carcinogenesis. While high-salt intake is a known risk factor for gastric cancer development, we determined the effects of high salt on gastric chemical carcinogenesis in COX-2 transgenic (TG) mice. COX-2 TG mice were developed in C57/BL6 strain using the full-length human cox-2 complementary DNA construct. Six-week-old COX-2 TG and wild-type (WT) littermates were randomly allocated to receive alternate week of N-methyl-N-nitrosourea (MNU, 240 p.p.m.) in drinking water or control for 10 weeks. Two groups of mice were further treated with 10% NaCl during the initial 10 weeks. All mice were killed at the end of week 50. Both forced COX-2 overexpression and high-salt intake significantly increased the frequency of gastric cancer development in mice as compared with WT littermates treated with MNU alone. However, no additive effect was observed on the combination of high salt and COX-2 expression. We further showed that MNU and high-salt treatment increased chronic inflammatory infiltrates and induced prostaglandin E2 (PGE2) production in the non-cancerous stomach. Whereas high-salt treatment markedly increased the expression of inflammatory cytokines (tumor necrosis factor-{alpha}, interferon-{gamma}, interleukin (IL)-1β and IL-6) in the gastric mucosa, COX-2 overexpression significantly altered the cell kinetics in the MNU-induced gastric cancer model. In conclusion, both high salt and COX-2 overexpression promote chemical-induced gastric carcinogenesis, possibly related to chronic inflammation, induction of PGE2, disruption of cell kinetics and induction of inflammatory cytokines.

Abbreviations: COX, cyclooxygenase; IFN, interferon; IL, interleukin; MNU, N-methyl-N-nitrosourea; mPGES, microsomal prostaglandin E synthase; PCR, polymerase chain reaction; PGE2, prostaglandin E2; TG, transgenic; TNF, tumor necrosis factor; WT, wild-type

Received January 22, 2008; revised June 17, 2008; accepted June 22, 2008.


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