MAGE-A9和MAGE-A11基因在乳腺癌组织中的表达及其临床意义  

Expression of melanoma antigen genes in human breast cancer: Association with major demographic and pathophysiologic variables and effect of drug treatment

作　　者：侯淑芸[1,2] 桑梅香[2] 单保恩[2] 

机构地区：[1]河北医科大学第三医院肿瘤科,河北石家庄050051 [2]河北医科大学第四医院科研中心,河北石家庄050011

出　　处：《中国肿瘤生物治疗杂志》2014年第4期428-436,共9页Chinese Journal of Cancer Biotherapy

基　　金：河北省自然科学基金资助项目(No.H2012206077)~~

摘　　要：目的:探讨黑素瘤抗原MAGE-A9和MAGE-A11在乳腺正常组织、乳腺良性病变、乳腺癌组织中的表达以及甲基化酶抑制剂5-氮杂-2'-脱氧胞苷(5-Aza-2’-deoxycytidine,5-Aza-CdR)和组蛋白去乙酰化酶抑制剂曲古抑菌素A(TSA)对MAGEA9和MAGE-A11基因表达的影响。方法:应用RT-PCR和免疫组化方法检测60例乳腺正常组织、60例乳腺良性病变及60例乳腺癌组织(标本均取自河北医科大学第四医院乳腺中心2007年11月至2008年5月乳腺手术治疗患者)中MAGE-A9和MAGE-A11 mRNA及其蛋白的表达,分析其与乳腺癌患者临床病理学特征的关系。RT-PCR检测乳腺癌细胞MCF-7、MDA-MB-231经5-Aza-CdR和TSA单独或联合作用后MAGE-A9和MAGE-A11 mRNA表达量的变化。结果:乳腺癌组织中MAGE-A9mRNA和蛋白阳性表达率分别为45%(27/60)和43.3%(26/60),MAGE-A11 mRNA和蛋白阳性表达率分别为66.7%(40/60)和63.3%(38/60),而乳腺正常组织及良性病变组织中均未发现MAGE-A9、MAGE-A11 mRNA及其蛋白的表达。MAGE-A9、MAGE-A11 mRNA和蛋白的表达与乳腺癌患者的年龄、病理类型、临床分期、肿瘤大小、淋巴转移、瘤栓及孕激素受体的表达均无明显关系(P>0.05),但与人表皮生长因子受体2(HER-2)和雌激素受体(ER)的表达有关(P<0.05)。未经药物处理的MCF-7、MDA-MB-231细胞未见MAGE-A9和MAGE-A11 mRNA表达;单用5-Aza-CdR处理后可见MAGE-A9和MAGE-A11基因重新表达,联合应用5-Aza-CdR和TSA处理可使MAGE-A9、MAGE-A11基因的表达量进一步增加(P<0.05);而TSA单独处理对基因表达没有影响(P>0.05)。结论:乳腺癌组织中MAGE-A9和MAGE-A11的表达与ER和HER-2的表达有关,5-AzaCdR单用或联合应用TSA可诱导和增强MAGE-A9和MAGE-A11 mRNA的重新表达,说明DNA的去甲基化和组蛋白乙酰化可能是调控人类肿瘤细胞MAGE表达的重要机制。Objective： The purpose of our study was to analyze the expression of melanoma antigen genes MAGE-A9 and MAGE-A11 in benign and malignant breast cancer specimens and in breast cancer cell lines following drug treatment.Methods： Tissue specimens were obtained from tumor-free breast（ n = 60）,benign breast cancer（ n = 60） and malignant breast cancer（ n = 60）,respectively. The mRNA abundance and protein content of MAGE-A9 and MAGE-A11 in these specimens were determined by RT-PCR and immunohistochemistry respectively and were analyzed for their associations with the major demographic,physiologic and pathologic variables. To examine the influence of chemotherapeutic drugs on MAGEs in breast cancer,MCF-7 and MDA-MB-231 cells were treated with 5-Aza-2 ＇-deoxycytidine（ 5-Aza-CdR）,a DNA methylase inhibitor,and trichostatin A（ TSA）,a histone deacetylase inhibitor,either each alone or both together,and mRNA levels of MAGE-A9 and MAGE-A11 were assessed by RT-PCR. Results： MAGE-A9 and MAGE-A11 transcripts were detected in 45% and 66. 7% of breast cancer specimens respectively and MAGE-A9 and MAGE-A11 proteins in43. 3% and 63. 3% of cancer specimens,respectively. MAGE-A9 and MAGE-A11 expression was positively correlated with the expression of estrogen receptor（ ER） and human epidermal growth factor receptor 2（ HER-2） in cancer specimens（ P 0. 05）. Neither transcripts nor proteins of MAGE-A9 and MAGE-A11 were detected in normal control specimens. While 5-Aza-CdR alone induced the expression of MAGE-A9 and MAGE-A11 in the test cell lines,TSA alone showed no effects. However,TSA was able to enhance 5-Aza-CdR-induced MAGE-A transcription（ P 0. 01）. Conclusion： MAGE-A9 and MAGE-A11 are tumor-specific antigens. Both DNA hypermethylation and histone deacetylation are possible mechanisms underlying MAGE-A9 and MAGE-A11 gene silencing.

关 键 词：乳腺癌 MAGE-A9 MAGE-A11 5-氮杂-2'-脱氧胞苷 曲古抑菌素A 

分 类 号：R737.9[医药卫生—肿瘤] R730.23[医药卫生—临床医学]