MAGE-A1和MAGE-A3在脑胶质瘤组织中的表达及其临床意义

Expression and clinical significance of melanoma antigen genes MAGE-A1 and MAGE-A3 in glioma tissues

目的:探讨黑色素瘤抗原基因-A1(MAGE-A1)和MAGE-A3在脑胶质瘤组织中的表达及其临床意义。方法:选取2006年1月至2010年1月河北医科大学第四医院神经外科手术切除的78例脑胶质瘤组织标本和15例车祸死亡捐献者的正常脑组织标本。用RT-PCR法检测胶质瘤组织中MAGE-A1和MAGE-A3的表达,分析其表达水平与患者预后的关系;用MSP-PCR术检测MAGE-A1和MAGE-A3基因启动子区的甲基化状态,分析两者表达与甲基化之间的关系;用RT-PCR法检测胶质瘤U251和U87细胞中MAGE-A1和MAGE-A3表达以及经DNA甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷(5-Aza-CdR)和组蛋白去乙酰化酶抑制剂曲古抑菌素A(TSA)联合作用后两者的表达水平。结果:78例胶质瘤组织中MAGE-A1和MAGE-A3 mRNA阳性表达率分别为65.34%和38.46%,而在15例正常脑组织中未发现2种m RNA表达。MAGE-A1阳性组患者5年生存率较阴性组低(P<0.05)。MAGE-A1和MAGE-A3基因启动子区去甲基化水平与其在mRNA水平上的表达均有显著的相关性(均P<0.01)。未经5-Aza-CdR和TSA处理的U87细胞未见MAGE-A1和MAGE-A3 mRNA的表达,U251细胞则有少量表达。单独给予TSA不能引起MAGE-A1和MAGE-A3基因的表达激活,单独给予5-Aza-CdR或与TSA合用可以引起该2个基因的表达激活,且两者合用的作用优于单独给药。结论:脑胶质瘤组织中有不同程度的MAGE-A1和MAGE-A3基因表达,MAGE-A1基因表达与患者的预后不良相关。DNA启动子区甲基化和组蛋白乙酰化是MAGE-A1和MAGE-A3基因表达激活的重要机制。

Objective:To detect the expressions of melanoma antigen genes MAGE-A1 and MAGE-A3 in glioma tissues and to explore their clinical significance.Methods:Seventy-eight surgically resected glioma specimens and 15 normal brain tissue samples from donors suffered traffic accidence were collected at the Department of Neurosurgery,the Fourth Hospital of Hebei Medical University between January 2006 and January 2010,and the mRNA expressions of MAGE-A1 and MAGE-A3 in collected tissues were detected with RT-PCR;their associations with the overall survival of patients were also analyzed.The promoter methylation status of the two genes was observed with methylation specific PCR,and the relationship between the gene expressions and promoter methylation status was analyzed.The expressions of MAGE-A1 and MAGE-A3 genes in U251 and U87 glioma cell lines were detected by RT-PCR before and after the treatment with DNA methyltransferase inhibitor 5-aza-CdR and/or histone deacetylase inhibitor trichostatin A(TSA).Results:The positive expression rates of MAGE-A1 and MAGE-A3 genes in glioma tissues were 65.34%and 38.46%,respectively;however,the two genes were not detected in 15 cases of normal brain tissues.The 5-year overall survival of patients in MAGEA1 positive expression group was shorter than that of negative expression group(P<0.05).There was significant correlation between the mRNA expressions of two genes and their promoter methylation status(all P<0.01).There was no mRNA expressions of MAGEA1 and MAGE-A3 in U87 cells untreated with 5-Aza-CdR and TSA,but a small amount of MAGE-A1 mRNA and MAGE-A3 mRNA were detected in U251 cells.TSA alone could not activate the expression of MAGE-A1 and MAGE-A3 genes.5-Aza-CdR alone or in combination with TSA could activate the expression of both genes,and the combined effect was better than that of single administration.Conclusion:There are different degrees of MAGE-A1 and-A3 expression in glioma tissues,and the expression of MAGE-A1 is a negative prognostic factor for glioma patients.DNA promoter methylation and histone acetylation are important mechanisms of the activation of MAGE-A1 and MAGE-A3 expression.