Omega-6/Omega-3 Fatty Acid Ratio and Tumorigenesis

Omega-6/Omega-3 脂肪酸比例与肿瘤发生

• 批准号: 7146999
• 负责人: JING X KANG
• 金额: $ 24.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146999
• 关键词: balance; eicosanoids; fats; fatty acids; genetically modified animals; laboratory mouse; neoplasm /cancer; omega 3 fatty acid; tissues

DESCRIPTION (provided by applicant): Although recent research suggests a link between the ratio of omega-6 (n-6) to omega-3 (n-3] fatty acids and cancer risk, the question as to whether a high n-6/n-3 ratio (>15), as found in most Western people, promotes tumorigenesis or if a balanced n-6/n-3 fatty acid ratio can reduce cancer development remains to be clarified in well-qualified experimental animal models. My lab has recently generated a novel transgenic mouse model that expresses the C. elegans fat-1 gene capable of converting n-6 to n-3 fatty acids, which is absent in wild type mice. These transgenic animals are characterized by an abundance of n-3 fatty acids and a balanced n-6/n-3 fatty acid ratio (1:1) in their tissues and organs, whereas wild type mice have a ratio of > 30 when maintained on the same diet high in n-6 and deficient in n-3 fatty acids. Use of these transgenic animals can avoid potential confounding factors of diet and will provide more reliable evidence on the effects of n-3 fatty acids and n-6/n-3 ratio. Our pilot experiments showed a marked difference in tumor formation and growth of B16 melanoma between wild type and fat-1 transgenic mice. This exciting observation led us to hypothesize that a balanced n-6/n-3 fatty acid ratio may have a protective effect against cancer development, and that this anticancer effect is induced by changes in cancer-related gene expression mediated by certain eicosanoids or lipid mediators. Specific aims are: 1) To determine the tumorigenicity and metastasis of B16 melanoma cells implanted in the fat-1 transgenic and wild type mice; 2) To characterize gene expression patterns of the tumor cells and stromal tissues in the fat-1 transgenic and wild type mice using a microarray technology; and 3) To determine if changes in eicosanoid biosynthesis are responsible for the effects on gene expression and tumor growth. Several approaches including microarray and lipidomics will be used to identify the involved mediators. Information derived from these studies will increase our understanding of the importance of n-3 fatty acids as well as n-6/n-3 fatty acid ratio in cancer prevention and help guide dietary advice.

描述（由申请人提供）：虽然最近的研究表明 omega-6 (n-6) 与 omega-3 (n-3] 脂肪酸的比例与癌症风险之间存在联系，但在大多数西方人中发现的高 n-6/n-3 比例 (>15) 是否会促进肿瘤发生，或者平衡的 n-6/n-3 脂肪酸比例是否可以减少癌症的发展，这一问题仍有待在合格的实验动物中得到澄清 模型。我的实验室最近生成了一种新型转基因小鼠模型，该模型表达秀丽隐杆线虫 fat-1 基因，该基因能够将 n-6 脂肪酸转化为 n-3 脂肪酸，而野生型小鼠中不存在这种基因。这些转基因动物的特点是其组织和器官中含有丰富的 n-3 脂肪酸和平衡的 n-6/n-3 脂肪酸比例 (1:1)，而野生型小鼠的比例 > 30 维持高 n-6 脂肪酸但缺乏 n-3 脂肪酸的相同饮食。使用这些转基因动物可以避免潜在的饮食混杂因素，并将为 n-3 脂肪酸和 n-6/n-3 比率的影响提供更可靠的证据。我们的初步实验表明，野生型和 fat-1 转基因小鼠之间的 B16 黑色素瘤肿瘤形成和生长存在显着差异。这一令人兴奋的观察使我们推测 平衡的 n-6/n-3 脂肪酸比例可能对癌症发展具有保护作用，这种抗癌作用是由某些类二十烷酸或脂质介质介导的癌症相关基因表达的变化引起的。具体目的是： 1）确定植入fat-1转基因和野生型小鼠体内的B16黑色素瘤细胞的致瘤性和转移性； 2) 利用微阵列技术表征fat-1转基因小鼠和野生型小鼠肿瘤细胞和基质组织的基因表达模式； 3) 确定类二十烷酸生物合成的变化是否对基因表达和肿瘤生长产生影响。包括微阵列和脂质组学在内的多种方法将用于鉴定所涉及的介质。从这些研究中获得的信息将增加我们对 n-3 脂肪酸以及 n-6/n-3 脂肪酸比率在癌症预防中的重要性的理解，并有助于指导饮食建议。