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首页> 外文期刊>The Journal of Nutritional Biochemistry >Use of a novel genetic mouse model to investigate the role of folate in colitis-associated colon cancer
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Use of a novel genetic mouse model to investigate the role of folate in colitis-associated colon cancer

机译：使用新型遗传小鼠模型研究叶酸在结肠炎相关结肠癌中的作用

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Inflammatory bowel disease (IBD) patients are at high risk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate-binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 weeks containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1/; RFC1/) fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1/) and littermate wild-type mice (P<.05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (three- to fourfold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 weeks after carcinogen injection. The number of high multiplicity aberrant crypt foci per centimeter of colon was significantly elevated (P<.05) in compound Folbp1/; RFC1/ (3.5pl0.4) mice as compared to Folbp1/ (1.9pl0.3) and wild-type control mice (1.1pl0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer.
机译：炎症性肠病（IBD）患者罹患叶酸缺乏和结肠癌的风险很高。由于很难研究与叶酸介导的肿瘤的发生和发展有关的微妙的全球性和特定于基因的表观遗传机制，因此，我们通过靶向还原型叶酸载体（RFC1）和叶酸结合蛋白（Folbp1）基因，生成了转基因小鼠模型。给转基因小鼠喂食半纯日粮8周，其中含有正常（2 mg）或不足（0.1 mg叶酸/ kg饮食）叶酸水平。与杂合子（Folbp1 /）和同窝野生型小鼠（P <.05）相比，饲喂充足叶酸饮食的复合杂合小鼠（Folbp1 /; RFC1 /）血浆血浆中的叶酸浓度降低。相反，在结肠粘膜中未观察到差异。尽管血浆高半胱氨酸水平没有改变，但低叶酸饮食的摄入在所有动物模型中均显着降低了血浆和组织叶酸水平（三至四倍）。为了阐明叶酸状况与炎症相关的结肠癌之间的关系，给动物注射了乙氧基甲烷，然后在饮用水中进行了葡聚糖硫酸钠处理。给小鼠饲喂正常的叶酸饮食，并在致癌剂注射后5周将其终止。化合物Folbp1 /中每厘米结肠的高多样性异常隐窝灶的数量显着增加（P <.05）。与Folbp1 /（1.9pl0.3）和野生型对照小鼠（1.1pl0.1）相比，RFC1 /（3.5pl0.4）小鼠。这些数据表明，消融叶酸转运的两种受体/载体介导的途径增加了发生与炎症相关的结肠癌的风险。

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