Abstract
BackgroundChronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. To shed light on the alterations in global gene expression in the background of inflammation-related colon cancer and gain further insights into the molecular mechanisms underlying inflammation-related colon carcinogenesis, we conducted a comprehensive DNA microarray analysis using our model.MethodsMale ICR mice were given a single ip injection of azoxymethane (AOM, 10 mg/kg body weight), followed by the addition of 2% (w/v) dextran sodium sulfate (DSS) to their drinking water for 7 days, starting 1 week after the AOM injection. We performed DNA microarray analysis (Affymetrix GeneChip) on non-tumorous mucosa obtained from mice that received AOM/DSS, AOM alone, and DSS alone, and untreated mice at wks 5 and 10.ResultsMarkedly up-regulated genes in the colonic mucosa given AOM/DSS at wk 5 or 10 included Wnt inhibitory factor 1 (Wif1, 48.5-fold increase at wk 5 and 5.7-fold increase at wk 10) and plasminogen activator, tissue (Plat, 48.5-fold increase at wk 5), myelocytomatosis oncogene (Myc, 3.0-fold increase at wk 5), and phospholipase A2, group IIA (platelets, synovial fluid) (Plscr2, 8.0-fold increase at wk 10). The notable down-regulated genes in the colonic mucosa of mice treated with AOM/DSS were the peroxisome proliferator activated receptor binding protein (Pparbp, 0.06-fold decrease at wk 10) and the transforming growth factor, beta 3 (Tgfb3, 0.14-fold decrease at wk 10). The inflammation-related gene, peroxisome proliferator activated receptor γ (Pparγ 0.38-fold decrease at wk 5), was also down-regulated in the colonic mucosa of mice that received AOM/DSS.ConclusionThis is the first report describing global gene expression analysis of an AOM/DSS-induced mouse colon carcinogenesis model, and our findings provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies against carcinogenesis.
Highlights
Chronic inflammation is well known to be a risk factor for colon cancer
We found an over-expression of β-catenin, COX-2 and inducible nitric oxide synthase (iNOS) in the colonic neoplasms induced by the treatment of AOM and dextran sodium sulfate (DSS) in mice in our previous immunohistochemical studies [5,6,7], other numerous and attractive gene alterations became apparent in the present study
Nuclear factor-kappaB (NF-κB) is a transcription factor that plays a crucial role in inflammation, immunity, cell proliferation, apoptosis, and tumorigenesis [51]
Summary
Chronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. The development and progression of colon carcinogenesis in both humans and rodents are known to be caused by the accumulation of cancer-related gene alterations, which results in their altered expression. Such genes include oncogenes, tumor suppressor genes, and mismatch repair genes [1,2]. Tumor suppressor genes, and mismatch repair genes [1,2] These changes could affect the expression of a variety of downstream genes such as those involved in the cell cycle, apoptosis, adhesion, and angiogenesis [3]. The immunohistochemical expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and β-catenin is markedly elevated in the AOM-induced CRC in rats [2]
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