Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk

描述（由申请人提供）：结直肠癌是美国第三大常见癌症，也是癌症相关死亡的第二大原因。慢性炎症和基因毒性自由基是结直肠癌发生的因素。因此，我们的长期目标是确定和评估可以通过直接调节氧化应激和慢性炎症来降低结直肠癌风险的生活方式和饮食因素。二十碳五烯酸是一种 omega-3 多不饱和脂肪酸，主要存在于海鱼中，并且在动物模型中始终表现出癌症抑制活性。二十碳五烯酸具有抗炎作用，而花生四烯酸（一种 omega-6 多不饱和脂肪酸）则具有促炎作用。我们的总体假设是，膳食中花生四烯酸与二十碳五烯酸比例增加的个体患结直肠腺瘤的风险会增加，并且这种增加的风险是通过促炎类二十烷酸和增加的氧化应激介导的。本研究计划的具体目的是： 1) 检验红细胞磷脂膜花生四烯酸与二十碳五酸比率越高与结直肠腺瘤风险增加相关的假设； 2) 检验以下假设：尿中 F2-异前列腺素水平的增加与结直肠腺瘤风险增加相关，而尿中 F3-异前列腺素水平增加与结直肠腺瘤风险降低相关； 3) 检验以下假设：花生四烯酸与二十碳五烯酸的比例越大，前列腺素 E2 和尿 F2-异前列腺素水平升高，尿 F3-异前列腺素水平降低。为了实现这些目标，我们将使用田纳西州结直肠息肉研究收集的数据，对 700 例非晚期结直肠腺瘤、350 例晚期结直肠腺瘤病例和 1050 例无息肉对照进行病例对照研究。我们的研究团队具有完成这些目标的独特资格，因为该研究所需的所有样本和临床数据都是作为正在进行的田纳西州结直肠息肉研究的一部分收集的，该研究是美国最大的基于结肠镜检查的腺瘤病例对照研究。此外，我们范德比尔特大学的同事是类二十烷酸研究的全球领导者。这些实验的结果将有助于我们了解二十碳五酸对人类结直肠癌的保护能力以及这种作用的潜在机制。 公共卫生相关性：结直肠癌是美国癌症相关死亡的第二大原因。鱼和鱼油补充剂中含有的 Omega-3 脂肪酸因其抗炎特性而被越来越多的人食用。本研究的目的是确定 omega-3 脂肪酸是否可以降低结直肠腺瘤的风险并减少炎症和氧化应激生物标志物的产生。

DESCRIPTION (provided by applicant):Colorectal cancer is the third most common cancer and the second leading cause of cancer related mortality in the United States. Chronic inflammation and genotoxic free radicals are contributors to colorectal carcinogenesis. As such, our long-term goals are to identify and evaluate lifestyle and dietary factors that can reduce the risk of colorectal cancer through direct modulation of oxidative stress and chronic inflammation. Eicosapentanoic acid is an omega-3 polyunsaturated fatty acid found predominately in marine fish and has consistently demonstrated cancer inhibitory activity in animal models. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas while an increase in urinary levels of F3-isoprostanes is associated with a decreased risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes and decreased levels of urinary F3-isoprostanes. To complete these aims we will perform a case-control study of 700, non-advanced colorectal adenomas, 350 advanced colorectal adenoma cases and 1050 polyp-free controls using data collected as part of the Tennessee Colorectal Polyp Study. Our research team is uniquely qualified to complete these aims as all samples and clinical data needed for the study have been collected as part of the on-going Tennessee Colorectal Polyp Study, the largest colonoscopy-based adenoma case-control study in the United States. In addition, our colleagues at Vanderbilt University are global leaders in eicosanoid research. The results from these experiments will contribute to our understanding of the colorectal cancer protective ability of eicosapentanoic acid in humans as well as potential mechanisms underlying this effect. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer related mortality in the United States. Omega-3 fatty acids, as found in fish and fish oil supplements, are being increasingly consumed because of their reported anti-inflammatory properties. The purpose of this study is to determine if omega-3 fatty acids reduce the risk of colorectal adenomas and diminishes the production of inflammatory and oxidative stress biomarkers.