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最常见的癌症，也是导致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。二十碳五烯酸是一种主要存在于海鱼中的omega-3多不饱和脂肪酸，在动物模型中一直显示出抑制癌症的活性。二十碳五烯酸具有抗炎作用，而花生四烯酸，一种ω -6多不饱和脂肪酸，具有促炎作用。我们的主要假设是，饮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，这种风险的增加是通过促炎的二十碳烷酸和氧化应激的增加来介导的。本研究方案的具体目的是：1)验证红细胞磷脂膜花生四烯酸与二十碳五烯酸比值越大与结直肠腺瘤风险增加相关的假设；2)验证尿中f2 -异前列腺素水平升高与结直肠腺瘤风险增加相关的假设，而尿中f3 -异前列腺素水平升高与结直肠腺瘤风险降低相关的假设；3)验证花生四烯酸与二十碳五烯酸比值升高与前列腺素E2和尿f2 -异前列腺素水平升高以及尿f3 -异前列腺素水平降低相关的假设。为了完成这些目标，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。我们的研究团队是唯一有资格完成这些目标的，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，我们范德比尔特大学的同事在类二十烷研究方面处于全球领先地位。这些实验结果将有助于我们了解二十碳五烯酸对人类结直肠癌的保护能力以及这种作用的潜在机制。

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.