丁酸钠对小鼠大肠癌的防治作用及其对甲基化酶的影响  

Preventive and therapeutic effects of sodium butyrate through down-regulating DNA methyltransferase on colorectal cancer in mice

作　　者：王霞[1] 陆嵘[1] 房静远[1] 

机构地区：[1]上海交通大学医学院附属仁济医院上海市消化疾病研究所,200001

出　　处：《中华消化内镜杂志》2007年第1期53-57,共5页Chinese Journal of Digestive Endoscopy

基　　金：基金项目：国家重点基础研究（973项目）专项经费资助（2005CB522408）;上海市重点学科建设资助项目（Y0205）

摘　　要：目的通过观察丁酸钠（NaBu）对二甲肼（DMH）诱发小鼠大肠癌的防治作用及其对抑癌基因p21^WAF1甲基化酶的影响，探讨乙酰化酶抑制剂防治肿瘤的分子机制。方法80只S-ICR小鼠随机均分4组：空白对照组、DMH造模组、NaBu对照组、DMH＋NaBu组。记录小鼠一般情况，分别于造模后18周、20周、22周每组处死小鼠2只，24周时全部处死。大体及镜下观察肠道肿瘤发生情况和组织学变化，逆转录-聚合酶链反应（RT-PCR）检测p21^WAF1 mRNA表达，定量PCR检测Dnmtl、Dnmt3a、Dnmt3b基因的表达。结果NaBu对小鼠无毒副作用；DMH＋NaBu组小鼠大肠癌发生率（25％）较DMH造模组（95％）明显降低（P〈0．05），肿瘤大小和数目亦显著低于造模组，且大肠癌的病理进展慢。DMH造模组肿瘤组织中较正常对照组甲基化酶水平升高3～4倍，抑癌基因p21^WAF1低表达；与造模组比较NaB组p21^WAF1表达增加，并伴有甲基化酶Dnmt1和Dnmt 3b mRNA降低（P〈0．05）。结论NaBu对DMH诱发的小鼠大肠癌具有一定防治作用，这与激活抑癌基因p21^WAF1表达、降低甲基化酶Dnmtl和Dnmt3b表达有关。Objective To explore the anti-cancer mechanisms of histone deacetylase inhibitor in mice with colorectal cancer induced by dimethylhydrazine （DMH）. Methods Eighty female S-ICR mice were randomly divided into 4 groups,group A, normal control; group B, DMH induced colorectal cancer; group C, NaBu control ; group D, NaBu intervention during carcinogenesis. The bloody stool and weight were observed, and two mice in each group were sacrificed at the 18^th, 20^th, 22^nd week, the rest were sacrificed at the 24＇h week. The macroscopic and histological changes of the colorectum were evaluated and scored. The expression of p21wan , Dnmtl, Dnmt3a and Dnmt3b was determined by RT-PCR and real-time PCR. Results NaBu had no obviously toxic and can improve the weight of emaciation. The tumor incidence was significantly lower in group D compared with group B （25% vs 95%, P 〈0. 05 ）, and the number and size of individual neoplasms were also reduced significantly （ P 〈 0. 05 ）, and the progression of tumorigenesis was delayed by NaBu. The levels of Dnmts were increased 3-4 fold and p21^WAF1 was down-regulated in colorectal cancer in group B compared with that in normal tissue in group A, while NaBu can recover the expression of p21^WAF1 , accompanied with the decrease of Dnmtl/3b mRNA. Conclusion A treatment regimen of NaBu in drinking water was effective to reduce the incidence of colorectal cancer in mice. The mechanism may be related to up-expression of p21^WAF1 and down-regulation of Dnmtl and Dnmt3b.

关 键 词：丁酸盐 直结肠肿瘤 1 2-二甲肼 P21^WAF1 DNA甲基化酶 

分 类 号：R735[医药卫生—肿瘤]