N-3/n-6多不饱和脂肪酸（PUFAs）在膳食中的比例减少是引起肥胖和大肠癌发生的重要原因，但PUFAs影响这一过程的机制尚未阐明。课题组前期研究中发现n-6或n-3 PUFAs可分别激活或抑制大肠癌细胞哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，fat-1(使n-6转化为n-3 PUFAs的酶)转基因可明显抑制APCmin/+小鼠mTORC1活性、降低血脂并减少大肠癌发生，提示n-3或n-6 PUFAs可通过调节mTOR通路与血脂水平抑制或促进大肠癌发生。本项目拟通过大肠上皮特异敲除TSC1、Raptor小鼠(使mTORC1过度激活或抑制)、fat-1转基因APCmin/+与fat-1-SCID小鼠与细胞模型，探讨mTORC1与血脂在介导PUFA影响大肠癌发生中的作用与机制，为n-3PUFAs抑制大肠癌的机制提出新观点，为饮食中增加n-3 PUFAs防治大肠癌提供依据。

The decreased proportion of dietary n-3/n-6 polyunsatuated fatty acids(PUFAs) is a major cause of obesity and and colorectal tumorigenesis. However, the underlying molecular mechanisms are not clearn. Our prelimiary data demonstrated that n-6 PUFAs strongly activated mammalian target of rapamycin (mTOR) signaling while n-3 PUFAs inhibited mTOR in colorectal cancer cells. Importantly, reduced mTOR activity, plasma lipids level and colorectal tumorigenesis were observed in fat-1 (desaturase that converts n-6 to n-3 PUFAs endogenously) transgenic APCmin/+ mice compared with littermate controls. These results implicate that n-3/n-6 PUFAs may regulate colorectal tumorigenesis through mTOR signaling and plasma lipids. Using large intestine-specific TSC1 and Raptor knockout mice (mTOR is specifically activated or inhibited in colorectal epithelial cells), fat-1 transgenic SCID and fat-1 transgenic APCmin/+ mice and colorectal cancer cells as models, this project aims to investigate the role and mechanisms of mTOR signaling and plasma lipids in regulation of colorectal tumorigenesis by n-3/n-6 PUFAs. This study will provide novel mechanisms for potentiation of colorectal tumorigenesis by dietary factors, and provide evidence for prevention and treatment of colorectal cancer by dietary n-3 PUFAs.

N-3/n-6多不饱和脂肪酸（PUFAs）在膳食中的比例减少是引起肥胖和大肠癌发生的重要原因，但PUFAs影响这一过程的机制尚未阐明。课题组前期研究中发现n-6或n-3 PUFAs可分别激活或抑制大肠癌细胞哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，fat-1(使n-6转化为n-3 PUFAs的酶)转基因可明显抑制APCmin/+小鼠mTORC1活性、降低血脂并减少大肠癌发生，提示n-3或n-6 PUFAs可通过调节mTOR通路与血脂水平抑制或促进大肠癌发生。本项目通过fat-1-APCmin/+(内源性转化n-6 PUFAs为n-3 PUFAs的肠癌小鼠),大肠上皮特异敲除TSC1、Raptor小鼠(使mTORC1过度激活或抑制)与细胞模型，探讨了PUFAs通过mTORC1抑制溃疡性结肠炎和结肠癌的作用和机制。 本研究发现，fat-1- APCMin/+双转基因小鼠相对于APCMin/+小鼠结肠癌发生率显著降低，贫血症状明显缓解。此外，无论在APC突变的结肠癌细胞系及敲低APC的正常肠上皮细胞系中，内源性和外源性的n-3 PUFAs均可通过显著抑制mTORC1的活性从而抑制细胞的增殖并促进其凋亡。fat-1- APCMin/+双转基因小鼠相对于APCMin/+小鼠血脂水平更低，而体外实验也证实n-3 PUFAs可抑制脂肪前体细胞中的mTORC1活性并抑制其成脂分化。本研究还发现，结肠上皮细胞特异性的mTORC1活性可通过环氧合酶2(COX-2)促进IL-1、IL-6和IL-23等炎症因子的表达，从而加剧溃疡性结肠炎。反之，n-3 PUFAs则可抑制结肠上皮细胞中的mTORC1活性并缓解溃疡性结肠炎。本研究为在饮食中增加n-3 PUFAs防治溃疡性结肠炎及大肠癌提供了理论依据。