eicosapentaecnoic acid是什么意思_百度知道
eicosapentaecnoic acid是什么意思
我有更好的答案
等待您来回答
下载知道APP
随时随地咨询
出门在外也不愁乳腺癌是世界范围内女性最常见的恶性肿瘤，严重威胁女性的生命与健康。随着生活方式的变化，尤其是膳食结构的日趋“西化”，包括中国在内的一些发展中国家妇女乳腺癌的发病率逐年升高。研究表明，乳腺癌与膳食、营养因素，尤其与膳食脂肪摄入密切相关。尽管对膳食、脂肪酸与乳腺癌之间关系的研究已有大量报道，但人群研究由于各地膳食模式的不同、受试人群的差异性，以及研究质量控制等因素，结果往往不尽相同。细胞和动物实验研究发现，不同种类的脂肪酸在肿瘤发生、发展过程中产生的影响各不相同，如n-6多不饱和脂肪酸（polyunsaturated fatty acid, PUFA）和n-3PUFA在乳腺癌形成过程中发挥的作用正好相反，前者可促进乳腺癌的发生和癌细胞的生长，而后者则有抗肿瘤及诱导乳腺癌细胞凋亡的作用，但PUFA影响乳腺癌发生发展的分子机制尚不明了。乳腺癌作为一种激素依赖性肿瘤，雌激素在其发生、发展过程中起着至关重要的作用。研究发现，雌激素主要通过受体依赖途径和非受体依赖途径促进乳腺癌的发生、发展。雌激素与细胞内雌激素受体（estrogen receptor, ER）结合，通过线粒体或细胞核内ER介导的信号通路促进细胞增殖、抑制细胞凋亡，影响乳腺癌的发生。在非受体依赖途径中，雌激素通过其代谢产物导致细胞DNA损伤并诱发癌症。由于ER阴性乳腺癌比ER阳性乳腺癌恶性度更高也更难治疗，雌激素通过非受体途径促进乳腺癌发生的机制研究更具有重要现实意义。芳香化酶（cytochrome P-45019, CYP19）是雌激素生物合成的关键限速酶，其活性的改变直接影响内源性雌激素的生成。雌激素经过第一相和第二相代谢反应，生成具有不同性质的代谢产物。其中，经过人类细胞色素P4501B1（cytochrome P-4501B1,CYP1B1）代谢生成的4-羟雌二醇（4-hydroxyestradiol,4-OH E2）被认为是雌激素通过非受体依赖途径致癌过程中重要的内源性致癌物。4-OH E2在体内氧化还原过程中产生醌和半醌等自由基可与DNA共价结合，引起DNA损伤。儿茶酚甲基转移酶（catechol-O-methyl transferase, COMT）将4-OH E2甲基化转变为水溶性的4-MeO E2排出体外，催化2-OH E2甲基化反应生成具有抗癌活性的2-MeO E2，降低致癌的醌类物质生成。因此，对雌激素代谢过程中关键酶的调控可能是影响雌激素通过非受体依赖途径促进乳腺癌发生的重要因素，我们推测CYP1B1可能是其中一个重要的靶点。以往开展的关于脂肪酸影响雌激素水平及其生物效应的研究较少。有研究提示，PUFA对雌激素合成、代谢酶的表达可能存在不同的调节作用，然而该类研究只局限于PUFA代谢产物前列腺素E2（prostaglandin E2, PGE2）/PGE3的生物效应，因此脂肪酸通过雌激素途径影响乳腺癌发生的机制仍不十分清楚。为了探讨雌激素代谢调节在n-6/n-3PUFA促进/抑制乳腺癌细胞增殖的差异性作用，本研究选择乳腺癌MDA-MB-231细胞（ER阴性）为研究对象，采用CCK-8法、荧光实时定量PCR（real-time fluorescence quantitative PCR）、蛋白免疫印迹、siRNA干扰等实验技术，观察二十碳五烯酸（eicosapentaenoic acid, EPA, n-3PUFA）和二十碳四烯酸（arachidonic acid,AA, n-6PUFA）两种不同PUFA对乳腺癌细胞增殖和雌激素代谢相关酶表达的影响，同时通过沉默CYP1B1基因，进一步研究上述两种PUFA对乳腺癌细胞增殖作用影响的变化，以探讨雌激素代谢酶的差异性调节在不同PUFA影响乳腺癌细胞增殖中的作用。主要实验结果和结论如下：1.以不同浓度（20、40、60、80和100μmol/L）EPA和AA处理雌激素受体阴性（ER-）乳腺癌MDA-MB-231细胞，CCK-8法检测细胞增殖功能改变，发现EPA能有效抑制乳腺癌细胞生长，而AA显著促进乳腺癌细胞生长，并呈显著的剂量-效应关系；2.一定剂量AA处理MDA-MB-231细胞能升高其雌激素代谢酶CYP19和CYP1B1mRNA表达，降低COMT mRNA表达，从而导致雌激素代谢相关致癌物生成增多；而相同剂量的EPA则降低MDA-MB-231细胞CYP19和CYP1B1mRNA表达，升高COMTmRNA表达。表明不同种类的PUFA对乳腺癌细胞雌激素代谢相关酶的基因表存在明显差异性调节；3. MDA-MB-231乳腺癌细胞通过siRNA干扰技术有效沉默CYP1B1表达24h后，再经PUFA处理24h，结果显示，siRNA转染能显著抑制CYP1B1mRNA和蛋白表达（mRNA表达水平下降了80±3.67%，蛋白水平下降了85±2.58%，P$$0.05），而灭活雌激素代谢相关致癌物的酶COMT mRNA和蛋白表达水平均有明显升高，其中经EPA处理的细胞COMT表达升高最明显。提示CYP1B1表达沉默能明显上调COMT的表达，从而减少雌激素代谢相关致癌物的产生；4. CYPB1表达沉默显著抑制乳腺癌MDA-MB-231细胞的增殖，细胞数量在转染24h、36h和48h后分别降低了(30±6.76)%、(33±6.91)%和(35±5.87)%。CYP1B1正常表达的乳腺癌细胞经EPA处理后增殖能力受到抑制，而AA则促进乳腺癌细胞的增殖；CYPB1表达沉默的乳腺癌细胞经EPA处理后细胞数量不降反升，AA对乳腺癌细胞的增殖促进作用亦被削弱。表明CYP1B1表达沉默能显著降低乳腺癌MDA-MB-231细胞增殖能力，且该基因的沉默逆转EPA对乳腺癌细胞增殖的抑制
Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancerdeath among women worldwide. Breast cancer incidence rates have been rising in manydeveloping countries including China most likely due to lifestyle changes associated withwesternization. Breast cancer risk is associated with some potentially modifiable factors suchas dietary and nutritional factors. Above all, consumption of dietary fat is closely related toincrease risk of breast cancer. However, research on the relationship between dietary fattyacids and breast cancer risk has been done a lot. Results of epidemiological studies can not beconsistent partly due to differences in dietary pattern, research methods and quality control.Researches in vitro/vivo agree that different types of fatty acids produce different effects oncarcinogenesis. The role of n-6polyunsaturated fatty acids (PUFA) and n-3PUFA played incarcinogenesis is just the opposite. The former can promote growth of cancer cells, while thelatter inhibits growth and induces apoptosis of cancer cells. But the molecular mechanisms arestill unclear.Breast cancer is a kind of hormone–dependent tumors. Estrogen is linked to breastcancer incidence. The molecular mechanisms underlying the estrogen–inducedcarcinogenesis are to stimulate cell proliferation via estrogen receptor (ER)–mediatedhormonal activity and to generate metabolites which lead to increased mutation rates orchromosome abnormalities via non ER–mediated pathways. Because breast cancer lackingER is usually more advanced and more difficult to treat than ER+breast cancer, to study themechanism of estrogen carcinogenesis via ER–independent pathways is very important.Aromatase (cytochrome P-45019, CYP19) is the rate-limiting enzyme in estrogenbiosynthesis. Its activity directly affects the generation of endogenous estrogen. Estrogensundergo phase I and II metabolism by which they are biotransformed into metabolites with different characteristics. Among them,4-hydroxyestradiol (4-OH E2) is considered to be oneof the most important endogenous carcinogens.4-OH E2can generate quinone andsemiquinone in vivo redox which can covalently bind to DNA and cause DNA damage.Catechol-O-methyl transferase (COMT) catalyzes the methoxylation of4-OH E2to form itsO-methyoxy estrogens (4-MeO E2) which is water-soluble and can be excreted. Estrogenmetabolism in different sites of reaction can directly affect the characters of the metabolites.Therefore, the regulation of key enzymes in estrogen metabolism may affect estrogencarcinogenesis.Studies suggest that n-6and n-3PUFA may regulate the expression of estrogenmetabolic enzymes. But these researches are only limited to PUFA metabolites ProstaglandinE2(PGE2)/PGE3or endometrial stromal cells. The mechanisms of fatty acids influencebreast cancer through the estrogen pathway are still unclear.To explore the relationship between n-6/n-3PUFA promoting/inhibiting proliferation ofbreast cancer cells and estrogen metabolic pathways, we used estrogen receptor-negative (ER-)breast cancer MDA-MB-231cells to analyze the effects of arachidonic acid (AA, n-6PUFA)and eicosapentaecnoic acid (EPA, n-3PUFA) on proliferation of breast cancer cells andexpressions of estrogen metabolic enzymes through CCK-8cell counting assay, qPCR(real-time fluorescence quantitative PCR), Western Blotting and RNA interference methods.Then we observed COMT mRNA expression and cell proliferation after RNA interferenceand PUFA treatment. Finally, we drew the conclusion that PUFAs effected proliferation ofbreast cancer cells through different regulations on estrogen metabolic enzyme CYP1B1expression.The main results and final conclusions were summarized as followings:1. Breast cancer cells MDA-MB-231were treated with EPA and AA in differentconcentrations (20,40,60,80and100μmol/L). The cell proliferation was detected by cellcounting kit-8(CCK-8) assay. We found that EPA inhibited MDA-MB-231cell proliferationdoes-dependently, while
本类论文推荐
本类求购排行
作者：刘洁琼&&年度：2011
作者：叶兆祥&&年度：2011
作者：任莎莎&&年度：2012
作者：牟鹏&&年度：2012
作者：张慧&&年度：2012
作者：王洪飞&&年度：2012
作者：王刚&&年度：2012
作者：袁园&&年度：2012
作者：周琼&&年度：2012
作者：蔡忠良&&年度：2012