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

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...

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Published in:Carcinogenesis (New York) 2008-08, Vol.29 (8), p.1648-1654
Main Authors: Leung, Wai K., Wu, Kai-chun, Wong, Christine Y. P., Cheng, Alfred S. L., Ching, Arthur K. K., Chan, Anthony W. H., Chong, Wilson W. S., Go, Minnie Y. Y., Yu, Jun, To, Ka-Fai, Wang, Xin, Chui, Y. L., Fan, D. M., Sung, Joseph J. Y.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Cell Division
Cyclooxygenase 2 - genetics
DNA - genetics
Female
Gastroenterology. Liver. Pancreas. Abdomen
Genetic Predisposition to Disease
Humans
Medical sciences
Methylnitrosourea - toxicity
Mice
Mice, Transgenic
Oviducts - enzymology
Pseudopregnancy - enzymology
Sodium Chloride, Dietary - toxicity
Stomach Neoplasms - chemically induced
Stomach Neoplasms - enzymology
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary: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-α, interferon-γ, 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.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgn156