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

简介(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。慢性炎症和遗传毒性自由基是结直肠癌发生的重要因素。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。二十碳五酸是一种omega-3多不饱和脂肪酸，主要存在于海鱼中，在动物模型中一直显示出抑制癌症的活性。二十碳五酸具有抗炎作用，而花生四烯酸是一种omega-6多不饱和脂肪酸，具有促炎作用。我们的主要假设是，花生四烯酸和二十碳五酸的饮食比例增加的人患结直肠腺瘤的风险将增加，这种增加的风险是通过促炎性二十碳六烯酸和增加的氧化应激来调节的。这项研究建议的具体目的是：1)测试红细胞膜磷脂膜花生四烯酸与二十碳五烯酸比率增加与结直肠腺瘤风险增加相关的假设；2)测试尿F2-异前列腺素水平升高与结直肠腺瘤风险增加相关，而F3-异前列腺素尿量增加与结直肠腺瘤风险降低相关的假设；3)测试较大的花生四烯酸与二十碳五烯酸比率与前列腺素E2和尿液F2-异前列腺素水平升高以及F3-异前列腺素水平降低有关的假说。为了实现这些目标，我们将使用田纳西州大肠息肉研究中收集的数据，对700例非进展期结直肠腺瘤、350例进展期结直肠腺瘤病例和1050例无息肉对照进行病例对照研究。我们的研究团队是唯一有资格实现这些目标的人，因为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，这是美国最大的基于结肠镜检查的腺瘤病例对照研究。此外，我们在范德比尔特大学的同事是二十烷类化合物研究的全球领导者。这些实验的结果将有助于我们理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：在美国，结直肠癌是癌症相关死亡的第二大原因。在鱼和鱼油补充剂中发现的omega-3脂肪酸正在被越来越多的人消费，因为据报道它们具有抗炎特性。这项研究的目的是确定omega-3脂肪酸是否降低了结直肠腺瘤的风险，并减少了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.