Gene expression analysis of a Helicobacter pylori-infected and high-salt diet-treated mouse gastric tumor model: identification of CD177 as a novel prognostic factor in patients with gastric cancer

Abstract

BackgroundHelicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.MethodsTo find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis.ResultsThe multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival.ConclusionsThese results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.

Porcine β-Defensin 2 Attenuates Inflammation and Mucosal Lesions in Dextran Sodium Sulfate–Induced Colitis

“…The mucus-containing cells were stained purple-red. Morphometric analyses of colons were performed using an image analysis program (28).…”

Mouse models for gastric cancer: Matching models to biological questions

“…For instance, H. pylori infection of INS‐GAS mice, a strain transgenically expressing gastrin from a rat insulin promoter fragment (see succeeding discussion), confers a greater gastric tumor incidence in males than in females, consistent with human epidemiological studies indicating a higher prevalence of GC in men . Likewise, the carcinogenic link between infection and dietary salt and nitrates/nitrites intake has been demonstrated in C57/BL6 mice, which develop more pronounced gastric atrophy and a greater risk of adenocarcinomas following infection with H. pylori and a high‐salt diet . Finally, because gastric atrophy results from infection associated with the outgrowth of commensal bacteria that is enabled by the loss of acid‐producing cells, the composition of the gut microbiota is considered another risk factor for GC.…”

Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer

“…When administered with MNNG or Nitroquinolone-1-oxide (NQO), sodium chloride promotes stomach carcinogenesis in the rats [85, 86] in a dose-dependent manner [87]. A high-salt diet also enhances the multiplicity of gastric tumors in MNU-treated mice and synergizes with the transforming effects of a Helicobacter infection [88]. Therefore the available data from experimental rodent models clearly supports the concept that high salt intake alone does not induce but rather increases the risk for gastric neoplasia.…”