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Carcinogenesis Advance Access published online on July 7, 2008
Carcinogenesis, 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 Leung, Kai-chun Wu, Christine YP Wong, Alfred SL Cheng, Arthur KK Ching, Anthony WH Chan, Wilson Chong, Minnie YY Go, Jun Yu, Ka-Fai To, Xin Wang, YL Chui, DM Fan and Joseph JY Sung

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

Correspondence to: Wai K. Leung, MD, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, Fax: +852 2637 3852. Email: dr_wkleung{at}alumni.cuhk.net

COX-2 over-expression is involved in gastric carcinogenesis. Whilst 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 cDNA 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 ppm) in drinking water or control for 10-week. Two groups of mice were further treated with 10% sodium chloride during the initial 10 weeks. All mice were sacrificed at the end of 50-week. Both forced COX-2 over-expression and high salt intake significantly increased the frequency of gastric cancer development in mice as compared to 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 PGE2 production in the non-cancerous stomach. While high salt treatment markedly increased the expression of inflammatory cytokines (TNF-{alpha}, IFN-{gamma}, IL-1β and IL-6) in the gastric mucosa, COX-2 over-expression 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.

Received January 22, 2008; revised June 18, 2008; accepted June 22, 2008.


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