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

Abstract

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 E(2) (PGE(2)) 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)-1 beta 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 PGE(2), disruption of cell kinetics and induction of inflammatory cytokines.

Runx3 at the interface of immunity, inflammation and cancer

“…As indicated earlier, normal gastric epithelial cells do not express Runx3 [12,22,26] and it has been reported that MNUinduced gastric tumors in mice are associated with chronic infiltration of inflammatory cells and that inflammation promotes MNU-induced gastric tumors [107]. Moreover, it has been shown that gastric cancer development in mice transgenic for Wnt1, Ptgs2 and Ptges (Gan mice) is dependent on TNFα and tumor formation could be rescued in TNFα −/− mice by transfer of bone marrow-derived DCs from TNFα +/+ mice, which infiltrated the tumors [108].…”

Cyclooxygenase-2 and Gastric Cancer

“…In a different approach, wild-type or COX-2 transgenic mice were treated with MNU. Whereas COX-2 overexpression alone did not lead to tumor development, the tumor incidence after MNU treatment was almost double in the COX-2 transgenic mice, suggesting a role of tumor promotion for COX-2 [91]. Also, gastric tumor multiplicity was higher in K19-C2mE mice that were treated with MNU and H. pylori compared to treated wild-type mice [92].…”

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

“…To this end, we have previously conducted extensive research and discovered an array of molecular regulators associated with stomach cancer development. [13][14][15][23][24][25] In particular, we recently demonstrated a causal relationship between H. pylori infection and aberrant DNA methylation in the host genome by cross-species epigenomics analysis, and revealed that epigenetic silencing of the antitumorigenic transcriptional regulator FOXD3 is a major mechanism responsible for the H. pylori-induced gastric carcinogenesis. 16,17 Here we provide new evidence that GDF1, which functions to protect gastric epithelial cells against malignant transformation by upholding SMAD signaling (Figures 3 and 4), is also susceptible to epigenetic silencing in the majority of mouse and human gastric cancers (Figures 1, 2 and 5).…”