Suzuki Rikako, Miyamoto Shingo, Yasui Yumiko, Sugie Shigeyuki, Tanaka Takuji
Department of Oncologic Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, Japan.
BMC Cancer. 2007 May 17;7:84. doi: 10.1186/1471-2407-7-84.
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. 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.
Male 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.
Markedly 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 gamma (Ppargamma 0.38-fold decrease at wk 5), was also down-regulated in the colonic mucosa of mice that received AOM/DSS.
This 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.
慢性炎症是结肠癌的一个众所周知的危险因素。此前我们建立了一种新型的炎症相关结肠癌发生小鼠模型，该模型有助于研究炎症在结肠癌发生中的作用。为了阐明炎症相关结肠癌背景下全球基因表达的变化，并进一步深入了解炎症相关结肠癌发生的分子机制，我们使用我们的模型进行了全面的DNA微阵列分析。
雄性ICR小鼠腹腔注射一次氧化偶氮甲烷（AOM，10mg/kg体重），然后在AOM注射1周后，在其饮用水中添加2%（w/v）葡聚糖硫酸钠（DSS），持续7天。我们对在第5周和第10周接受AOM/DSS、单独AOM、单独DSS处理的小鼠以及未处理小鼠的非肿瘤黏膜进行了DNA微阵列分析（Affymetrix基因芯片）。
在第5周或第10周给予AOM/DSS的结肠黏膜中显著上调的基因包括Wnt抑制因子1（Wif1，第5周增加48.5倍，第10周增加5.7倍）、组织型纤溶酶原激活剂（Plat，第5周增加48.5倍）、髓细胞瘤癌基因（Myc，第5周增加3.0倍）和磷脂酶A2，IIA组（血小板、滑液）（Plscr2，第10周增加8.0倍）。用AOM/DSS处理的小鼠结肠黏膜中显著下调的基因是过氧化物酶体增殖物激活受体结合蛋白（Pparbp，第10周下降0.06倍）和转化生长因子β3（Tgfb3，第10周下降0.14倍）。炎症相关基因过氧化物酶体增殖物激活受体γ（Ppargamma，第5周下降0.38倍）在接受AOM/DSS的小鼠结肠黏膜中也下调。
这是第一篇描述AOM/DSS诱导的小鼠结肠癌发生模型全球基因表达分析的报告，我们的发现为炎症相关结肠癌发生机制以及针对癌症发生的新型治疗和预防策略的建立提供了新的见解。
