Folic Acid Supplementation and Prevention of Colitis-Associated Colorectal Cancer

描述(由申请人提供)：美国于1996年开始实施常规的叶酸强化食品，以降低新生儿出生缺陷的风险。广泛的强化与补充相结合，导致叶酸的摄入量达到 比预期要高得多。有人担心，高叶酸摄入量可能会导致在这一任务完成后观察到的结直肠癌(CRC)发病率的增加。到目前为止，叶酸水平与结肠癌形成和进展之间的确切关系还没有明确的确定。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，这些患者有很强的CRC潜在易感性，经常需要叶酸补充。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。 伴发肿瘤。该实验的基本原理由初步数据提供，证实：1)与健康对照组相比，急性或慢性结肠炎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的多发性，叶酸水平显著升高；2)化学预防药剂5-氨基水杨酸降低血浆叶酸水平与肿瘤抑制直接相关，这为高叶酸补充可促进结肠癌的发生提供间接证据；3)体外以叶酸补充人结肠癌细胞可导致NF-kB转录活性增强。提出的研究假设是，膳食叶酸浓度与干预措施预防结肠炎相关性CRC的能力之间存在负相关，较高水平的叶酸增强了NF-kB信号并改变了DNA甲基化。在特定目标1中，在结肠炎形成后，给予不同水平的饮食叶酸对结肠炎和结肠的影响 肿瘤的形成将被评估。拟议的研究将在临床相关的偶氮甲烷/葡聚糖硫酸钠诱导的结肠炎相关肿瘤的小鼠模型中进行；该小组在十多年前建立了一个模型，并具有广泛的特征。将测量血浆和结肠粘膜总叶酸水平，并将其与组织炎症程度、肿瘤多样性和增殖指数相关联。在具体目标2中，将使用DREAM分析来评估不同浓度的叶酸对结肠粘膜(正常和炎症)DNA甲基化的影响，这是一种无偏见的全基因组方法。关于叶酸对结肠炎相关性结直肠癌发展的影响的拟议综合分析有望为建立UC患者使用叶酸补充剂的癌症预防指南提供信息，并为了解叶酸水平作为这一高危人群癌症易感性的信息生物标志物的潜在用途提供洞察力。

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.