Dietary Factors in Colon Cancer Prevention

描述(由申请人提供)： 该项目研究了饮食因素以大豆分离蛋白为营养范例，抑制大鼠和小鼠(并推断为人类)结肠癌的新机制。研究中的中心假说认为，饮食中的大豆分离蛋白降低了循环中的胰岛素水平，从而降低了结肠癌中造脂酶的表达，从而在结肠癌的发生和发展过程中减少了增殖，增加了细胞凋亡。SpragueDawley大鼠将被喂以高脂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(控制蛋白)或大豆分离蛋白(SPI)。在给予化学致癌物偶氮甲烷(AOM)后，这些饮食蛋白引起了肠道肿瘤指数的显著差异。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，以及d)结肠中造脂酶基因的表达(在肿瘤形成之前和期间)。当只在怀孕期间喂食大豆蛋白时，会影响成年后AOM诱导的后代肿瘤形成的结果(结肠癌的“营养规划”)。因此，饮食蛋白类型、脂肪合成酶基因的代谢调节与结肠癌之间的联系是有支持的。三个特定的目的将通过阐明饮食SPI对高脂喂养的肥胖大鼠结肠肿瘤发生的抑制作用；检测饮食SPI对高脂喂养大鼠和小鼠结肠肿瘤进展的抑制作用；以及调查肥胖诱导的胎儿程序性结肠肿瘤形成的机制来检验这些拟议的联系。所有这三个目标的重点都将放在脂肪生成酶基因上，作为肥胖状态下胰岛素和甲状腺素的下游促增殖和抗凋亡靶点。长期目标是利用大豆分离蛋白中存在的蛋白质/多肽和非蛋白质生物活性因子，以及针对下游造脂酶基因/途径，来加强人类结直肠癌和肥胖的预防策略。这些研究对改善超重/肥胖人群的健康和生活质量具有很强的翻译意义，这些人群有患结直肠癌的风险或苦恼。

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.