n-3PUFA联合5-FU对SW480细胞裸鼠皮下移植瘤的疗效观察

目的:建立人结肠癌SW480细胞裸鼠皮下移植瘤模型,观察n-3 PUFA联合5-FU对SW480细胞裸鼠皮下移植瘤的疗效.方法:SW480细胞裸鼠皮下移植瘤模型随机分成正常饲料组、5-FU组、n-3 PUFA高剂量组、n-3 PUFA低剂量组、n-3 PUFA对照组,除正常饲料组、5-FU组添加正常饲料外,其余各组添加不同含量的n-3 PUFA饲料,同时,各给药组腹腔注射5-FU(35 mg/kg),一周2次,连续3周,每次给药前称体重、测量肿瘤的长径和短径;末次给药后,处死动物,剥离肿瘤并称重;通过各组肿瘤的生长曲线和抑瘤率观察SW480细胞裸鼠皮下移植瘤的抑制效果.结果:与正常饲料组比较,n-3 PUFA高、低剂量组和5-FU组肿瘤平均体积显著性减小(P＜ 0.05);肿瘤平均重量明显减轻(P＜0.05).结论:n-3 PUFA联合5-FU对SW480细胞裸鼠皮下移植瘤有一定的抑瘤作用.     

n-3多不饱和脂肪酸的肿瘤治疗作用及其机制

0引言 n-3(ω-3)脂肪酸是一类第一个不饱和键出现在碳链甲基端第三位的多不饱和脂肪酸(polyunsaturated fatty acid,PUFA),它具有多种生物学功能,近年来其在肿瘤治疗中的作用尤其受到关注[1],它可能通过几种途径起作用,但确切机制尚不明确.其中核转录因子-кappaB(nuclear factor-кB,NF-кB)是它的靶因子之一,研究表明n-3 PUFA可通过抑制NF-кB活性起到抗肿瘤的作用.     

n-3多不饱和脂肪酸抗肿瘤机制的研究进展

n-3多不饱和脂肪酸（n-3PUFA）是包含多个双键的多聚不饱和脂肪酸,因为第1个双键出现在碳链甲基端的第3位,所以称之为n-3脂肪酸,也叫ω-3脂肪酸。n-3多不饱和脂肪酸主要包括α-亚麻酸（α-Linolenic acid,LNA）、二十碳五烯酸（Eicosap-entaenoic acid,EPA）和二十二碳六烯酸（Docosahexaenoic acid,DHA）。     

重庆市女性血浆游离脂肪酸组成谱及其与乳腺癌的相关性研究

背景与目的:脂肪酸与乳腺癌的关系的研究已广泛开展,但流行病学研究的结果不尽相同.本研究旨在通过检测重庆市女性血浆游离脂肪酸组成,分析其与乳腺癌发生之间的相关性.方法:在重庆市开展乳腺癌的病例-对照研究,收集458位乳腺癌患者(绝经前期女性268例,绝经后期女性190例)和健康人群789例(绝经前462例,绝经后327例).通过气相色谱法检测各组试验对象血浆游离脂肪酸的水平,使用SPSS 13.0软件比较各组血浆游离脂肪酸水平的差异,并分析不同脂肪酸暴露水平与乳腺癌发生风险的相关性.结果:绝经前、后女性血浆棕榈酸(C16:0) (OR=0.66和0.31)、总单不饱和脂肪酸(monounsaturated fatty acid,MUFA)(OR=0.59和0.39)及油酸(C18:1)n9(OR=0.54和0.42)水平升高显著降低乳腺癌的发病风险,而血浆总多不饱和脂肪酸(polyunsaturated fatty acid,PUFA) (OR=2.12和2.32)、总n-6 PUFA (OR=1.46和3.24)、亚油酸(C18:2)(OR=1.63和2.35)水平高,以及高n-6/n-3 PUFA比(OR=1.73和2.64)则增加乳腺癌的发病风险.此外,绝经前女性血浆硬脂酸(C18:0)水平高也能增加乳腺癌的发病风险(OR=2.53,95％CI=1.21～4.82,P=0.006).结论:重庆市女性乳腺癌患者的血浆游离脂肪酸组成有明显的改变,其中MUFA与乳腺癌的发生呈负相关,而n-6 PUFA和n-6/n-3 PUFA与乳腺癌的发生呈正相关,提示合理的膳食脂肪摄入可能降低乳腺癌的患病风险.     

n-3多不饱和脂肪酸在乳腺癌综合治疗中的作用

乳腺癌是一种异质性肿瘤,代谢异常在乳腺癌的发生、发展中起重要作用.n-3多不饱和脂肪酸(PUFA)可以通过多种途径改变乳腺癌细胞的脂肪酸代谢,调节癌基因和抑癌基因的表达,从而在乳腺癌的化疗、放疗、内分泌治疗和分子靶向治疗等综合治疗中起作用.     

结直肠癌多不饱和脂肪酸代谢与△6脱饱和酶关系的研究

目的 了解结直肠癌患者多不饱和脂肪酸（PUFA）代谢状况,探讨PUFA代谢与△6脱饱和酶（D6D）的关系.方法 检测38例结直肠癌患者血红细胞及61例结直肠癌手术切除标本肿瘤组织PUFA的水平,分析ω-6和ω-3代谢途径各脂肪酸比例、D6D指数及两者关联性.结果 结直肠癌患者血红细胞及组织标本ω-6 PUFA代谢占优势,ω-6/ω-3 PUFA总比例分别为4.89和10.15;亚油酸/亚麻酸（LA/ALA）比值分别为101.92和86.16; ω-6/ω-3 LC-PUFA分别为2.86和4.51.ω-6代谢途径中D6D指数在肿瘤组织（t=11.609,P=0.00）及血红细胞（t=-9.151,P=0.00）中均高于ω-3途径代谢.结论 结直肠癌患者PUFA代谢以ω-6PUFA占优势,ω-6脂肪酸代谢途径较ω-3代谢途径活跃,与结直肠癌的发生、发展有一定的关系,可能为结直肠癌的防治提供一种手段.     

Rho GTP酶在ω-3多不饱和脂肪酸抑制人前列腺癌PC-3细胞转移中的作用

背景与目的:近年来,多不饱和脂肪酸对肿瘤发生、发展影响的研究备受关注.本实验主要观察两种ω-3多不饱和脂肪酸(ω-3 polyunsaturated fatty acid,ω-3 PUFA)二十碳五烯酸(eicosapentaenoic acid,EPA)和二十二碳六烯酸(docosahexaenoic acid,DHA)对人前列腺癌细胞株PC-3转移的影响,并通过检测ω-3 PUFA对细胞内Rho GTP酶蛋白表达及细胞骨架重组影响,揭示Rho GTP酶在ω-3 PUFA抑制肿瘤转移中的作用.方法:MTT法观察ω-3 PUFA对PC-3细胞增殖能力的影响,体外粘附实验、侵袭实验和迁移实验观察ω-3 PUFA对肿瘤细胞转移的影响.Western blot法检测ω-3 PUFA对与细胞骨架重组相关的RhoA、Rac1、Rac2和Cdc42蛋白表达的影响.免疫荧光细胞化学法标记微丝和微管,激光共聚焦扫描显微镜观察ω-3 PUFA对细胞骨架重组的影响.结果:EPA及DHA均能抑制PC-3细胞增殖,增殖抑制率均随处理浓度增大和作用时间延长而增加.与对照组比较,60μmol/L的EPA或DHA处理后的PC-3细胞体外粘附性、侵袭性和迁移性均显著下降(P＜0.05).ω-3 PUFA能显著下调Rac1、Rac2和Cdc42蛋白表达(P＜0.05),并能明显影响细胞内微丝和微管细胞骨架的结构和分布.结论:ω-3 PUFA能够通过下调Rho GTP酶基因表达,抑制Rho GTP酶对细胞骨架重组的调控,导致细胞骨架结构改变,削弱肿瘤细胞的粘附性、侵袭性和迁移性,抑制PC-3细胞的转移.     

孕期和哺乳期n-3多不饱和脂肪酸对子代小鼠成年脑神经发生及凋亡的影响

目的探讨生命早期n-3多不饱和脂肪酸(n-3 polyunsaturated fatty acids,n-3 PUFAs)营养状态对成年期脑神经元发生及凋亡的影响。方法使用20只3-4 w龄清洁级C57BL/6J雌性小鼠,随机分为两组(10只/组),分别给予n-3 PUFAs缺乏和n-3 PUFAs饲料喂养;12-14 w龄时与雄性小鼠合笼交配繁殖。仔鼠生后21 d断乳时,随机挑选20只n-3 PUFAs缺乏组仔鼠用n-3 PUFAs饲料喂养,挑选等量n-3 PUFAs饲料组仔鼠用n-3 PUFAs缺乏饲料喂养,剩余仔鼠用与母鼠相同饲料继续喂养,至仔鼠3月龄时结束实验。小鼠麻醉处死后取全脑组织,采用脂肪酸甲酯化-气相色谱分析对脑脂肪酸进行测定;采用免疫组织化学技术对海马CA3区B淋巴细胞瘤-2蛋白(B-cell lymphoma-2,Bcl-2)、Bcl-2相关X蛋白(Bcl-2 associated X protein,Bax)和钙视网膜结合蛋白(Calretinin,CR)表达进行分析。结果与n-3 PUFAs缺乏饲料持续喂养的仔鼠相比,孕期和哺乳期n-3 PUFAs缺乏而断乳后给予n-3 PUFAs饲料喂养的仔鼠,成年后脑组织n-3 PUFAs含量明显升高(P<0.05),但Bcl-2、Bax和CR的表达量均未发生显著性变化,仍然低于n-3 PUFAs饲料持续喂养仔鼠的水平。孕期和哺乳期n-3 PUFAs饲料喂养而断乳后给予n-3 PUFAs缺乏饲料喂养的仔鼠,成年后脑组织n-3PUFAs含量较n-3 PUFAs饲料持续喂养的仔鼠明显降低(P<0.05);Bcl-2和CR的表达量高于n-3 PUFAs缺乏饲料持续喂养的仔鼠(P<0.05)。结论孕期和哺乳期保证适量n-3 PUFAs的摄入,有助于成年期脑神经元的发生,并减少神经元凋亡。     

孕期及哺乳期不同含量n-3多不饱和脂肪酸对子代成年期小鼠海马神经细胞凋亡相关因子的影响

目的观察母孕期及哺乳期不同含量n-3多不饱和脂肪酸（PUFAs）饲料对成年期仔鼠脑神经细胞凋亡的影响。方法使用6～8W龄清洁级C57BL／6J雌性小鼠,随机分为5组,每组10只,分别给予n-3 PUFAs缺乏和3种不同比例n-6／n-3PUFAs（n-6／n-3PUFAs比值分别为15：1、5：1、1：1）饲料及1种高含量鱼油n一3PUFAs饲料（n-6／n-3PUFAs比值为1：5）喂养。小鼠12～14W龄时雌雄合笼交配繁殖,仔鼠断乳后继续行母鼠相同饲料喂养,选取生后3m成年仔鼠用于实验。取脑进行组织固定,采用免疫组织化学技术对脑组织海马区Bcl-2和BaX表达进行定量分析。结果与n-3PUFAs缺乏组相比,n-3PUFAs饲料喂养组,尤其是13—6／n-3PUFAs比值（5：1）和（1：1）组小鼠海马CA3区神经细胞抗凋亡蛋白Bcl-2表达明显增加（P〈0．05）,而致凋亡蛋白Bax表达则显著降低（P〈0．05）。但高含量鱼油n一3PUFAs喂养组（即n-6／n-3PUFAs1：5组）与n一3PUFAs缺乏组相比未表现出显著性差异。结论孕期及哺乳期添加13—3PUFAs,尤其是n～6／n-3PUFAs比值在5～1：1之间时有助于减少成年仔鼠脑组织神经细胞凋亡的发生,而过高含量n-3PUFAs摄入则未对脑凋亡发生起到积极作用。     

结直肠癌组织脂肪酸及与相关肿瘤因子的分析

目的：分析结直肠组织多不饱和脂肪酸（PUFA）的成分水平,以及与相关肿瘤因子的相关性。方法：新鲜冷冻的肿瘤组织与正常组织取自2010—12—201i-03在中国人民解放军总医院普通外科行结直肠癌切除术的82例患者。应用气相色谱毛细管层析法检测组织中PUFA成分水平。并行酶联免疫技术测定组织中肿瘤相关细胞因子。结果：肿瘤组织中总（ω-6PUFA、亚油酸（LAC18：2）显著低于正常组织,P=0．00。总ω-3PUFA和花生三烯酸（DGLAC20：3）在肿瘤组织中显著增高,P=0．00。花生四烯酸（AAC20：4）／亚油酸（LA）及AA／总m-6PUFA在肿瘤组织中明显增高,P=0．00。同一患者肿瘤组织中前列腺素E2（PGE2）、血小板衍生因子（PDGF）、环氧化酶（COX-2）及血管内皮生长因子（VEGF）相比正常组织偏高。其中,PDGF、COX-2及VEGF差异有统计学意义（P=0．01,P=0．00）。在研究对象中,LA与COx-2呈负相关（r=-0．3244,P〈0．05）,AA／总ω-6PUFA、AA／LA（r=0．3083和0．3001,P〈0．05）。结论：结直肠癌及正常组织多不饱和脂肪酸的代谢存在差异,肿瘤组织中消耗m-6PUFA并产生代谢产物,有助于局部炎症微环境的产生,从而可能促进了肿瘤的发生及发展。     

Opposing effects of prepubertal low- and high-fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis

To determine whether dietary fat intake during childhood affects the later risk of developing breast cancer, we fed prepubertal rats between post-natal days 5 and 25 a low (16% energy) or high-fat (39% energy) diet composed mainly of n-6 or n-3 polyunsaturated fatty acids (PUFAs) originating either from corn oil or menhaden oil, respectively, in the ratios of 16-17:1 (n-6 PUFA diets) or 2-3:1 (n-3 PUFA diets). We also examined whether changes in risk are associated with perturbations in biological processes previously linked to fatty acid intake and breast cancer. Mammary tumorigenesis was induced by treating 50-day-old rats with the carcinogen 7,12-dimethylbenz[a]anthracene. When compared with the reference low-fat n-6 PUFA diet, prepubertal exposure to the low-fat n-3 PUFA diet decreased, whereas a high-fat n-3 PUFA diet increased mammary tumor incidence; the high-fat n-6 PUFA diet had no effect. Both the low and high-fat n-3 PUFA diets induced mammary epithelial differentiation by reducing the number of terminal end buds (TEBs) and increasing the presence of lobulo-alveolar structures. They also increased lipid peroxidation and reduced cyclooxygenase-2 activity. Prepubertal exposure to the low-fat n-3 PUFA diet increased apoptosis, determined using TUNEL assay, and reduced cell proliferation, determined using PCNA staining. In marked contrast, prepubertal exposure to the high-fat n-3 PUFA diet induced cell proliferation and inhibited apoptosis in the TEBs and lobular structures. The latter is consistent with the finding that pAkt, a survival factor that inhibits apoptosis, was elevated in their mammary glands. In summary, although prepubertal exposure to a low-fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast cancer risk.     

Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat

The mechanisms by which n-3 polyunsaturated fatty acids (PUFAs) decrease colon tumor formation have not been fully elucidated. Examination of genes up- or down-regulated at various stages of tumor development via the monitoring of gene expression relationships will help to determine the biological processes ultimately responsible for the protective effects of n-3 PUFA. Therefore, using a 3 x 2 x 2 factorial design, we used Codelink DNA microarrays containing approximately 9000 genes to help decipher the global changes in colonocyte gene expression profiles in carcinogen-injected Sprague Dawley rats. Animals were assigned to three dietary treatments differing only in the type of fat (corn oil/n-6 PUFA, fish oil/n-3 PUFA, or olive oil/n-9 monounsaturated fatty acid), two treatments (injection with the carcinogen azoxymethane or with saline), and two time points (12 hours and 10 weeks after first injection). Only the consumption of n-3 PUFA exerted a protective effect at the initiation (DNA adduct formation) and promotional (aberrant crypt foci) stages. Importantly, microarray analysis of colonocyte gene expression profiles discerned fundamental differences among animals treated with n-3 PUFA at both the 12 hours and 10-week time points. Thus, in addition to demonstrating that dietary fat composition alters the molecular portrait of gene expression profiles in the colonic epithelium at both the initiation and promotional stages of tumor development, these findings indicate that the chemopreventive effect of fish oil is due to the direct action of n-3 PUFA and not to a reduction in the content of n-6 PUFA.     

Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α

Liver tumors, particularly hepatocellular carcinoma (HCC), are a major cause of morbidity and mortality worldwide. The development of HCC is mostly associated with chronic inflammatory liver disease of various etiologies. Previous studies have shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) dampen inflammation in the liver and decrease formation of tumor necrosis factor (TNF)-α. In this study, we used the fat-1 transgenic mouse model, which endogenously forms n-3 PUFA from n-6 PUFA to determine the effect of an increased n-3 PUFA tissue status on tumor formation in the diethylnitrosamine (DEN)-induced liver tumor model. Our results showed a decrease in tumor formation, in terms of size and number, in fat-1 mice compared with wild-type littermates. Plasma TNF-α levels and liver cyclooxygenase-2 expression were markedly lower in fat-1 mice. Furthermore, there was a decreased fibrotic activity in the livers of fat-1 mice. Lipidomics analyses of lipid mediators revealed significantly increased levels of the n-3 PUFA-derived 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA) in the livers of fat-1 animals treated with DEN. In vitro experiments showed that 18-HEPE and 17-HDHA could effectively suppress lipopolysacharide-triggered TNF-α formation in a murine macrophage cell line. The results of this study provide evidence that an increased tissue status of n-3 PUFA suppresses liver tumorigenesis, probably through inhibiting liver inflammation. The findings also point to a potential anticancer role for the n-3 PUFA-derived lipid mediators 18-HEPE and 17-HDHA, which can downregulate the important proinflammatory and proproliferative factor TNF-α.     

Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells

Diets enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against breast cancer but biochemical mechanisms are unclear. Our studies showed that the n-3 fatty acid docosahexaenoic acid (DHA) up-regulated syndecan-1 (SDC-1) in human breast cancer cells, and we tested the hypothesis that DHA-mediated up-regulation of SDC-1 induces apoptosis. DHA was delivered to MCF-7 cells by n-3 PUFA-enriched low-density lipoproteins (LDL) or by albumin in the presence or absence of SDC-1 small interfering RNA. The n-3 PUFA induced apoptosis, which was blocked by SDC-1 silencing. We also confirmed that SDC-1 up-regulation and apoptosis promotion by n-3 PUFA was mediated by peroxisome proliferator-activated receptor gamma (PPAR gamma). Using a luciferase gene driven by either a PPAR response element or a DR-1 site present in the SDC-1 promoter, reporter activities were enhanced by n-3 LDL, DHA, and PPAR gamma agonist, whereas activity of a luciferase gene placed downstream of a mutant DR-1 site was unresponsive. Cotransfection with dominant-negative PPAR gamma DNA eliminated the increase in luciferase activity. These data provide strong evidence that SDC-1 is a molecular target of n-3 PUFA in human breast cancer cells through activation of PPAR gamma and that n-3 PUFA-induced apoptosis is mediated by SDC-1. This provides a novel mechanism for the chemopreventive effects of n-3 PUFA in breast cancer.     

Reducing endothelial NOS activation and interstitial fluid pressure with n-3 PUFA offset tumor chemoresistance

The aim of this study was to determine how n-3 polyunsaturated fatty acid (PUFAs) counteracted tumor chemoresistance by restoring a functional vascularization. Rats with chemically induced mammary tumors were divided into two nutritional groups: a control group and a group fed with an n-3 PUFA-enriched diet. Both groups were treated with docetaxel. Functional vascular parameters (ultrasounds, interstitial fluid pressure) were determined for both nutritional groups before (W(0)) and during docetaxel treatment [every 2 h up to 1 week (W(+1)) for interstitial fluid pressure, at W(+1) for Evans blue extravasation and at W(+2) and W(+6) for ultrasounds]. In vitro n-3 PUFA-induced changes in endothelial cell migration, permeability and phosphorylation of endothelial nitric oxide synthase were evaluated using human umbilical vein endothelial cells. Whereas docetaxel stabilized tumor growth in the rat control group, it induced a 50% tumor regression in the n-3 PUFA group. Ultrasounds parameters were consistently lower in the n-3 PUFA group at all time points measured, down to ～50% at W(+6). A single dose of docetaxel in the n-3 PUFA group markedly reduced interstitial fluid pressure from 2 h after injection up to W(+1) when Evans blue extravasation was increased by 3-fold. A decreased activation of endothelial nitric oxide synthase in tumors of the n-3 PUFA group, and in human umbilical vein endothelial cell cultured with n-3 PUFA, points toward a PUFA-induced disruption of nitric oxide signaling pathway. This normalization of tumor vasculature functions under n-3 PUFA diet indicates that such a supplementation, by improving drug delivery in mammary tumors, could be a complementary clinical strategy to decrease anticancer drug resistance.     

Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women: a prospective cohort study

Breast cancer is the most common cancer in women. Controversy exists regarding the role of dietary fat in breast cancer etiology. We investigated the association of dietary polyunsaturated fatty acids (PUFAs) and the ratio of n-6 PUFAs to marine-derived n-3 PUFAs with breast cancer risk in the Shanghai Women's Health Study, a prospective cohort study including 72,571 cancer-free participants at baseline. Dietary fatty acid intake was determined using food frequency questionnaires. We used Cox proportional hazards analysis to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for the association of breast cancer risk with dietary fatty acids consumption. In 583,998 person-years of follow-up, we identified 712 breast cancer cases. We found no association of breast cancer risk to dietary intake of linoleic acid, arachidonic acid, α-linolenic acid or marine-derived n-3 PUFA. We found a statistically significant interaction between n-6 PUFA intake, marine-derived n-3 PUFA intake and breast cancer risk (p = 0.008). Women with lower intake (the lowest tertile) of marine-derived n-3 PUFA and higher intake (the highest tertile) of n-6 PUFA had an increase risk for breast cancer (RR = 2.06; 95% CI = 1.27-3.34) compared to women with higher intake (the highest tertile) of marine-derived n-3 PUFAs and lower intake (the lowest tertile) of n-6 PUFAs after adjusting for potential confounders. The relative amounts of n-6 PUFA to marine-derived n-3 PUFAs may be more important for breast cancer risk than individual dietary amounts of these fatty acids.     

Opposing associations of serum n-3 and n-6 polyunsaturated fatty acids with colorectal adenoma risk: an endoscopy-based case-control study

Several human and animal studies have shown that n-3 polyunsaturated fatty acids (PUFA) might be associated with a decreased risk, whereas other studies showed that n-6 PUFA may be associated with an increased risk of colorectal cancer. However, results from these studies are not consistent. We evaluated the associations between serum n-3 and n-6 PUFA levels and colorectal adenoma risk in an endoscopy-based case-control study, conducted in The Netherlands between 1997 and 2002. We included 363 cases of colorectal adenomas and 498 adenoma-free controls. Serum fatty acids were measured in cholesteryl esters. Logistic regression models were used to calculate odds ratios (OR), which were adjusted for age, gender and alcohol intake. Total serum n-3 PUFA levels were inversely associated with colorectal adenoma risk, the OR comparing the third tertile with the first tertile was 0.67 [95% confidence interval (CI) 0.46-0.96, p for trend = 0.03]. Serum eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3) and the n-3/n-6 ratio were inversely associated with colorectal adenoma risk, but these were not statistically significant. In contrast, the risk of colorectal adenomas was increased by total n-6 PUFA with an OR of 1.68 (95% CI, 1.17-2.42, p for trend = 0.006) and by linoleic acid (LA; C18:2n-6) with an OR of 1.65 (95% CI, 1.15-2.38, p for trend = 0.007). This is the first observational study that simultaneously finds an inverse association of serum n-3 PUFA and a positive association of n-6 PUFA with colorectal adenoma risk.     

Unsaturated fatty acids intake and breast cancer risk: epidemiological data review

The relationship between fatty acids and breast cancer has been debated for long, because of the high frequency of breast cancer and the contradictory results from the numerous studies devoted to this issue. The present review includes case-control and prospective studies, according to specified methodological criteria, which estimated the exposure to monounsaturated fatty acids (MUFA) and n-6 and n-3 polyunsaturated fatty acids (PUFA) using dietary questionnaires or markers (plasma, erythrocytes, adipose tissue). The relationship between MUFA intake and breast cancer risk seems to depend on the contributing food : neutral or beneficial for vegetable oil, rather deleterious for animal products. Contrary to data from animal experiments, human studies do not show an increase of breast cancer risk with n-6 PUFA intake. Estimating the risk associated with alpha-linolenic acid appears difficult due to the incompleteness of food composition tables and studies on biomarkers remain few. The same applies to long-chain n-3 PUFA despite the suggestion of a decrease in risk, in agreement with animal studies. However, it is difficult in human to disentangle the effect of nutrient intake from that of contributing foods or even nutritional profile.     

Chemopreventive n-3 fatty acids activate RXRalpha in colonocytes

The underlying mechanisms by which n-3 polyunsaturated fatty acids (PUFA) exert a chemopreventive effect in the colon have not been elucidated. Retinoid X receptors (RXR) are a family of nuclear receptors implicated in cancer chemoprevention. Since docosahexaenoic acid (DHA), an n-3 PUFA enriched in fish oil, reduces colonocyte proliferation and enhances apoptosis relative to n-6 PUFA-treated cells, we determined whether DHA can serve as a specific ligand for RXRalpha activation relative to n-6 PUFA in colonocytes. In a mammalian one-hybrid assay, immortalized young adult mouse colonic (YAMC) cells were co-transfected with a yeast galactose upstream activating sequence (UAS)4-tk-Luciferase (Luc) reporter plasmid, plus either GAL4 DNA-binding domain fused to RXRalpha, retinoic acid receptor alpha or GAL4 alone, followed by an n-3, n-6 or n-9 fatty acid incubation. Luc activity levels were dose-dependently elevated only in n-3 PUFA (DHA)-treated RXRalpha. Since RXR homodimers and RXR/peroxisome proliferator-activated receptor (PPAR) heterodimers bind consensus direct repeat (DR1) motifs, YAMC and NCM460 (a normal human colonic cell line), were respectively, co-transfected with RXRalpha and DR1-Luc, followed by different PUFA treatment. Luc activity levels were increased (P < 0.05) only in DHA groups. The DHA-dependent induction of DR-1-Luc was reduced to basal levels upon RXRalpha antagonist-treatment, with no effect on PPARgamma antagonist-treatment. A role for select RXR isoforms in colonocyte biology was also determined by examining nuclear receptor mRNA levels in rat colon following dietary lipid and carcinogen exposure over time. RXRalpha, RXRbeta and RXRgamma were detected in rat colonic mucosa, and the levels of RXRalpha and RXRgamma were elevated in fish oil (n-3 PUFA) versus corn oil (n-6 PUFA) fed animals after 16 weeks. These data indicate that, RXRalpha, an obligatory component of various nuclear receptors, preferentially binds n-3 PUFA in colonocytes, and that the nuclear receptor targets for PUFA in the colon are modulated by dietary lipid exposure.