Dietary Factors in Colon Cancer Prevention

描述（由申请人提供）： 该项目研究了饮食因素的新机制，使用大豆分离蛋白作为营养范例，抑制大鼠和小鼠（以及推断人类）的结肠癌。研究中的中心假设假定，膳食大豆分离蛋白降低循环胰岛素水平，因此，结肠脂肪生成酶的表达，这反过来又导致结肠肿瘤发生和发展期间增殖减少和凋亡增加。Sprague-Dawley大鼠将喂食高脂肪饮食以诱导肥胖和高胰岛素血症。饮食将包含等量的酪蛋白（对照蛋白）或大豆分离蛋白（SPI）。这些膳食蛋白质引起显着差异后，肠道肿瘤指数的化学致癌物，氧化偶氮甲烷（AOM）管理。SPI抑制：a）异常隐窝病灶（ACF;结肠腺瘤/癌的中间终点生物标志物）的数量，B）结肠肿瘤的发生率，c）全身胰岛素水平，和d）结肠中脂肪生成酶基因的表达（在肿瘤发生之前和期间）。大豆蛋白，当只在怀孕期间喂养，影响后代中AOM诱导的肿瘤发生的结果，作为后来的成年人（结肠癌的“营养程序”）。因此，饮食蛋白质类型，脂质合成酶基因的代谢调节和结肠癌之间的联系得到了支持。三个具体目标将通过阐明膳食SPI对高脂喂养的肥胖大鼠结肠肿瘤发生的抑制作用;检查膳食SPI对高脂喂养的大鼠和小鼠结肠肿瘤进展的抑制作用;以及研究肥胖诱导的结肠肿瘤发生的胎儿编程机制来检查这些拟议的联系。所有三个目标的重点将是脂肪生成酶基因作为胰岛素和甲状腺素在肥胖状态下的下游促增殖和抗凋亡靶标。长期目标是利用大豆蛋白分离物中存在的蛋白质/肽和非蛋白质生物活性因子，以及下游脂肪生成酶基因/途径的靶向，以增强人类结肠直肠癌和肥胖预防策略。这些研究对于改善有结肠直肠癌风险或患有结肠直肠癌的超重/肥胖人群的健康和生活质量具有很强的转化意义。

DESCRIPTION (provided by applicant): This project studies novel mechanisms by which dietary factors, using soy protein isolate as the nutritional paradigm, inhibit colon cancers of the rat and mouse (and by inference human). The Central Hypothesis under study posits that dietary soy protein isolate reduces circulating insulin levels and as a consequence, colonic expression of lipogenic enzymes, which in turn confers reduced proliferation and increased apoptosis during colon tumor initiation and progression. Sprague-Dawley rats will be fed high fat diets to induce obesity and hyperinsulinemia. Diets will contain equal amounts of casein (control protein) or soy protein isolate (SPI). These dietary proteins elicited significant differences in intestinal tumor indices after administration of the chemical carcinogen, azoxymethane (AOM). SPI suppressed: a) numbers of aberrant crypt foci (ACF; intermediate end-point biomarker of colon adenomas/carcinomas), b) incidence of colon tumors, c) systemic insulin levels, and d) expression of lipogenic enzyme genes in colon (both prior to and during tumorigenesis). Soy protein, when fed only during pregnancy, influenced the outcome of AOM-induced tumorigenesis in the progeny as later adults ("nutritional programming" of colon cancer). Thus, there is support for linkages of dietary protein type, metabolic regulation of lipid synthetic enzyme genes, and colon cancer. Three Specific Aims will examine these proposed linkages by elucidating the inhibitory actions of dietary SPI on initiation of colon tumorigenesis in the high fat-fed, obese rat; examining the inhibitory actions of dietary SPI on colon tumor progression in the high fat-fed rat and mouse; and investigating mechanisms of obesity-induced fetal programming of colon tumorigenesis. Emphasis in all three Aims will be on lipogenic enzyme genes as downstream pro-proliferative and anti-apoptotic targets of insulin and thyroxine, in obese states. Long-term goals are to utilize proteins/peptides and non-protein bio-active factors present in soy protein isolates, and the targeting of downstream lipogenic enzyme genes/pathways, to augment human colo-rectal cancer- and obesity-prevention strategies. These studies have strong translational significance for improving the health and quality of life of the overweight/obese population at risk for or afflicted with colo-rectal cancer.