WWOX基因在贲门腺癌中的异常甲基化及其表达  

Aberrant methylation and expression of WWOX gene in gastric cardia adenocarcinoma

作　　者：郭炜[1] 董稚明[1] 郭艳丽[1] 杨植彬[1] 邝钢[1] 

机构地区：[1]河北医科大学第四医院肿瘤研究所,石家庄050011

出　　处：《肿瘤》2012年第4期275-280,共6页Tumor

基　　金：河北省医学科学研究重点课题计划(编号:20090465)

摘　　要：目的:探讨贲门腺癌(gastric cardia adenocarcinoma,GCA)中WWOX(WWdomain-containing oxi-doreductase)基因启动子区及第1外显子区的甲基化状态及其对表达的影响,并分析贲门腺癌中WWOX与Smad4(mothers against decapentaplegic homolog4)蛋白表达之间的关系。方法:分别应用甲基化特异性PCR和免疫组织化学法检测贲门腺癌组织及其相应癌旁组织中WWOX基因的甲基化和蛋白的表达情况;应用免疫组织化学法检测贲门腺癌组织及其相应癌旁组织中Smad4蛋白的表达。结果:贲门腺癌组织中WWOX基因启动子区(-382～-41bp)及第1外显子区(-27～+344bp)的甲基化率[26.4%(33/125)和23.2%(29/125)]显著高于其相应的癌旁常组织(0%和0%)(P<0.01),并与贲门腺癌TNM分期和上消化系统肿瘤家族史有关(P<0.05)。贲门腺癌组织中WWOX蛋白的表达阳性率显著低于相应癌旁组织(P<0.01),WWOX蛋白的表达与WWOX启动子区和第1外显子区甲基化状态之间呈负相关(r=-0.216,r=-0.255,P<0.05)。贲门腺癌组织中Smad4蛋白表达的阳性率(47.2%)显著低于相应癌旁组织(94.4%)(P<0.01),且与WWOX在贲门腺癌中的表达呈明显的正相关(r=0.622,P<0.01)。结论:WWOX基因启动子区及第1外显子区的高甲基化导致的基因表达下调可能在贲门腺癌中发挥重要作用。Objective： To investigate the methylation of promoter and exon 1 regions of WW domain-containing oxidoreductase （WWOX） gene and the expression of WWOX gene in gastric cardia adenocarcinoma（GCA）, and to evaluate the correlation between the expressions of WWOX protein and mothers against decapentaplegic homolog 4 （Smad4） protein. Methods： The methylation of WWOX gene in GCA tissues and the adjacent normal tissues was detected by methylation-specific polymerase chain reaction, and the expressions of WWOX and Smad4 proteins were determined by immunohistochemistry method. Results： The methylation rates of promoter （-382 to -41 bp） and exon 1 （-27 to ＋344 bp） regions of WWOX gene were 26.4% （33/125） and 23.2% （29/125） in GCA tissues, respectively, which were significantly higher than those in the adjacent normal tissues （0% and 0%） （P〈0.01）. The methylation frequency of WWOX gene was associated with TNM stage and family history of upper gastrointestinal cancers （P〈0.05）. The positive rate of WWOX protein in GCA tissues was lower than that in the adjacent normal tissues （P〈0.01）. The expression of WWOX protein was negatively associated with the methylation status of promoter and exon 1 regions of WWOX gene （r = -0.216, r = -0.255; P〈0.05）. The positive rate of Smad4 protein in GCA tissues （47.2%） was lower than that in the adjacent normal tissues （94.4%） （P〈0.01）, and the expression of Smad4 protein was positively associated with the expression of WWOX protein in GCA tissues （r = 0.622, P〈0.01）. Conclusion： Decreased expression of WWOX gene induced by hypermethylation of promoter and exon 1 regions may play an important role in the development of GCA.

关 键 词：胃肿瘤 DNA甲基化 基因表达 基因 WWOX Smad4 

分 类 号：R735.2[医药卫生—肿瘤]