Role Of Lipids In Colon, Breast, And Other Cancers

脂质在结肠癌、乳腺癌和其他癌症中的作用

• 批准号: 8149031
• 负责人: Thomas Eling
• 金额: $ 54.75万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149031
• 关键词: Breast; Colon; Lipids; Malignant Neoplasms; Role

The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit COX activity, reduce the incidence and mortality of colon cancer and reduce polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. We have recently discovered that the overexpression of COX-2 in a transgenic mouse model during embryonic development results in a number of physiological defects, ultimately resulting in the death of the fetus. The most dramatic effects were on skeletal development caused by the induction of apoptosis in the sclerotome of the transgenic embryos. This was a specific response not observed in other tissues. In addition, the sclerotomal accumulation of p53 protein is observed in transgenic embryos, suggesting that COX-2 may induce apoptosis via the up-regulation of p53. The aberrant COX-2 signaling during embryonic development is teratogenic and suggests a possible association of COX-2 with fetal malformations of unknown etiology.

花生四烯酸（AA）和亚油酸（LA）代谢的重要性得到动物和人类流行病学研究的支持，这些研究表明阿司匹林和其他非甾体抗炎药能够抑制COX活性，降低家族性息肉病患者结肠癌的发病率和死亡率，减少息肉。对啮齿动物的实验研究表明，非甾体抗炎药可以减少致癌物诱导的结肠肿瘤的大小和数量。前列腺素和其他脂质在结肠癌和其他癌症的发生和发展中起着重要作用，但其机制尚不清楚。我们最近发现，在胚胎发育过程中，转基因小鼠模型中COX-2的过表达会导致许多生理缺陷，最终导致胎儿死亡。对骨骼发育的影响最为显著的是诱导转基因胚胎核组细胞凋亡。这是一种在其他组织中未观察到的特异性反应。此外，在转基因胚胎中还观察到p53蛋白的硬化层积累，提示COX-2可能通过上调p53介导细胞凋亡。胚胎发育过程中异常的COX-2信号是致畸的，提示COX-2可能与病因不明的胎儿畸形有关。