Folic Acid Supplementation and Prevention of Colitis-Associated Colorectal Cancer

描述（由申请人提供）：1996年，美国实施了叶酸食品常规强化，以降低新生儿出生缺陷的风险。广泛的强化与补充相结合，导致叶酸的摄入水平， 远高于预期人们担心，高叶酸摄入量可能会导致本任务后观察到的结直肠癌（CRC）发病率增加。迄今为止，叶酸水平与结肠肿瘤形成和进展之间的确切关系尚未明确建立。此外，叶酸在溃疡性结肠炎（UC）患者中的作用受到的关注要少得多，这些患者具有很强的CRC潜在易感性，经常需要补充叶酸。这项研究的总体目标是评估不同浓度的叶酸对结肠炎发展的影响 相关瘤形成所提出的实验的原理由初步数据提供，所述初步数据证明：1）与健康对照相比，患有急性或慢性结肠炎的非荷瘤小鼠的血浆叶酸水平显著降低，并且随着疾病的进展和结肠炎相关CRC的多样性而增加; 2）化学预防剂5-氨基水杨酸引起的血浆叶酸水平的降低与肿瘤抑制直接相关，提供了高叶酸补充可促进结肠肿瘤发生的间接证据;和3）在体外用叶酸补充人结肠癌细胞导致增强的NF-κ B转录活性。拟议研究的假设是，叶酸的饮食浓度与干预预防结肠炎相关CRC的能力之间存在负相关性，较高水平的叶酸增强NF-κ B信号传导并改变DNA甲基化。在具体目标1中，在结肠炎建立后，给予不同水平的膳食叶酸对结肠炎症和结肠炎的影响。 评估肿瘤形成。拟议的研究将在诱导结肠炎相关肿瘤的临床相关氧化偶氮甲烷/葡聚糖硫酸钠小鼠模型中进行;该模型是该小组十多年前建立的，并已广泛表征。将测量总血浆和结肠粘膜叶酸水平，并将其与组织炎症程度、肿瘤多样性和增殖指数相关联。在Specifc Aim 2中，将使用DREAM测定（一种无偏倚的全基因组方法）评价不同浓度的叶酸对结肠粘膜（正常和炎症）DNA甲基化谱的影响。叶酸对结肠炎相关结直肠癌发展的影响的综合分析有望为UC患者使用叶酸补充剂的癌症预防指南的建立提供信息，并提供叶酸水平作为该高危人群癌症易感性的信息生物标志物的潜在效用的见解。

DESCRIPTION (provided by applicant): Routine fortification of food with folic acid was implemented in the U.S. in 1996 to reduce the risk of birth defects in newborns. Widespread fortification in combination with supplementation has led to the ingestion of folate at levels that are much higher than ever anticipated. Concern exists that high folic acid intake may contribute to the increase in colorectal cancer (CRC) incidence that was observed subsequent to this mandate. To date, the precise relationship between folate levels and colon tumor formation and progression has not been clearly established. Furthermore, much less attention has been given to the role of folate in patients with ulcerative colitis (UC) who have a strong underlying predisposition to CRC and frequently require folic acid supplementation. The overall goal of this study is to assess the effect of varying concentrations of folic acid on the development of colitis associated neoplasia. Rationale for the proposed experimentation is provided by preliminary data that demonstrate that: 1) plasma folate levels are reduced significantly in nontumor-bearing mice with acute or chronic colitis, as compared to healthy controls, and increase with both progression of disease and the multiplicity of colitis-associated CRC; 2) reductions in plasma folate levels by the chemopreventive agent 5-aminosalicylic acid correlate directly with tumor inhibition, providing indirect evidence that high folic acid supplementation may promote colon tumorigenesis; and 3) supplementation of human colon carcinoma cells with folic acid in vitro leads to enhanced NF-kB transcriptional activity. The hypothesis of the proposed studies is that an inverse association exists between dietary concentrations of folic acid and the ability of the intervention to prevent colitis-associated CRC, with higher levels of folic acid enhancing NF-kB signaling and altering DNA methylation. In Specific Aim 1, the effect of administering varying levels of dietary folic acid, after the establishment of colitis, on colonic inflammation and colon tumor formation will be assessed. The proposed studies will be performed in the clinically relevant azoxymethane/dextran sulfate-sodium mouse model of induced colitis-associated neoplasia; a model that this group established more than a decade ago and has characterized extensively. Total plasma and colonic mucosal folate levels will be measured and correlated with both the degree of tissue inflammation, tumor multiplicity, and proliferative index. In Specifc Aim 2, the impact of varying concentrations of folic acid on the DNA methylation profile of the colonic mucosa (normal and inflamed) will be evaluated using the DREAM assay, a non-biased genome-wide approach. The proposed comprehensive analysis of the effect of folic acid on the development of colitis-associated CRC is anticipated to inform the establishment of cancer preventive guidelines for the use of folic acid supplements in UC patients and provide insight into the potential utility of folate levels as an informative biomarker of cancer susceptibility inthis high-risk population.