Rao C V, Simi B, Wynn T T, Garr K, Reddy B S
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595, USA.
Cancer Res. 1996 Feb 1;56(3):532-7.
Epidemiological and laboratory animal model studies suggest that the effect of dietary fat in colon carcinogenesis depends not only on the amount but on its fatty acid composition. Animal model studies demonstrated that high dietary corn oil or safflower oil rich in omega-6 fatty acids increased the colon tumor promotion, whereas diets containing fish oil high in omega-3 fatty acids had no such enhancing effect. One of the mechanisms by which high dietary fat enhances colon carcinogenesis may be through the modulation of colonic mucosal phospholipase A2 (PLA2) and phosphatidylinositol-specific phospholipase C (PI-PLC), which are dominant pathways for arachidonic acid release and formation of eicosanoids. PI-PLC is also responsible for diacylglycerol formation and protein kinase C-dependent signal transduction and cell proliferation. In the present study, we investigated the modulating effect of high fat diets rich in omega-3 and omega-6 fatty acids on colonic mucosal PLA2, PI-PLC activities, and eicosanoid (prostaglandins and thromboxane B2) formation from arachidonic acid via cyclooxygenase (COX) during different stages of azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. At 5 weeks of age, groups of animals were fed the low-fat diet containing 5% corn oil. Beginning at 7 weeks of age, all animals except those intended for vehicle treatment received AOM s.c. once weekly for 2 weeks at a dose rate of 15 mg/kg body weight. Vehicle-treated groups received an equal volume of normal saline. One day after the second AOM or vehicle treatment, groups of animals were transferred to experimental diets containing 23.5% corn oil and 20.5% fish oil + 3% corn oil, whereas one group continued on the low-fat diet containing 5% corn oil. Groups of animals were then sacrificed at weeks 1, 12, and 36 after the second AOM-or saline-treatment. Colonic mucosa harvested at weeks 1, 12, and 36 and colonic tumors obtained at week 36 were analyzed for PLA2, PI-PLC, and eicosanoid formation from arachidonic acid by the action of COX. The results demonstrate that colon carcinogen treatment increases the activities of colonic mucosal PLA2 and PI-PLC and the formation of prostaglandins and thromboxane A2 from arachidonic acid through COX throughout the study period compared to saline-treated animals fed similar diets. The activities of PLA2, PI-PLC, and COX were significantly higher in colon tumors compared to colonic mucosa. These results also demonstrate that a high-fat diet containing corn oil increases colonic mucosal and tumor PLA2 and PI-PLC and the formation of prostaglandins and thromboxane B2 by the action of COX as compared to low dietary corn oil or a diet high in fish oil. The results of our study offer one of the mechanisms by which the amount and types of dietary fat modulate colon carcinogenesis.
流行病学和实验动物模型研究表明，饮食脂肪在结肠癌发生过程中的作用不仅取决于其数量，还取决于其脂肪酸组成。动物模型研究表明，富含ω-6脂肪酸的高剂量玉米油或红花油会促进结肠肿瘤的发展，而富含ω-3脂肪酸的鱼油饮食则没有这种促进作用。高剂量饮食脂肪促进结肠癌发生的机制之一可能是通过调节结肠黏膜磷脂酶A2（PLA2）和磷脂酰肌醇特异性磷脂酶C（PI-PLC），这是花生四烯酸释放和类花生酸形成的主要途径。PI-PLC还负责二酰基甘油的形成以及蛋白激酶C依赖性信号转导和细胞增殖。在本研究中，我们调查了富含ω-3和ω-6脂肪酸的高脂肪饮食对雄性F344大鼠在氧化偶氮甲烷（AOM）诱导的结肠癌发生不同阶段结肠黏膜PLA2、PI-PLC活性以及通过环氧化酶（COX）从花生四烯酸形成类花生酸（前列腺素和血栓素B2）的调节作用。5周龄时，将动物分组并喂食含5%玉米油的低脂饮食。从7周龄开始，除了准备进行溶剂处理的动物外，所有动物每周皮下注射一次AOM，持续2周，剂量为15mg/kg体重。溶剂处理组注射等量的生理盐水。在第二次AOM或溶剂处理后一天，将动物分组转移到含23.5%玉米油和20.5%鱼油+3%玉米油的实验饮食中，而一组继续喂食含5%玉米油的低脂饮食。然后在第二次AOM或生理盐水处理后的第1、12和36周处死动物。分析在第1、12和36周收获的结肠黏膜以及在第36周获得的结肠肿瘤中PLA2、PI-PLC以及通过COX作用从花生四烯酸形成类花生酸的情况。结果表明，与喂食类似饮食的生理盐水处理动物相比，在整个研究期间，结肠癌致癌物处理会增加结肠黏膜PLA2和PI-PLC的活性以及通过COX从花生四烯酸形成前列腺素和血栓素A2的量。与结肠黏膜相比，结肠肿瘤中PLA2、PI-PLC和COX的活性显著更高。这些结果还表明，与低剂量玉米油饮食或高剂量鱼油饮食相比，含玉米油的高脂肪饮食会增加结肠黏膜和肿瘤中PLA2和PI-PLC的活性以及通过COX作用形成前列腺素和血栓素B2的量。我们的研究结果提供了饮食脂肪的数量和类型调节结肠癌发生的一种机制。
