MAGE-A9 mRNA and protein expression in bladder cancer
MAGE-A9 mRNA and protein expression in bladder cancer
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DOI：
10.1002/ijc.22282
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发表时间：
2007-05-15
影响因子：
6.4
通讯作者：
Fradet, Yves
中科院分区：
文献类型：
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作者：
Picard, Valerie;Bergeron, Alain;Fradet, Yves
在先前的分析中，我们发现MAGE-AS是人类膀胱肿瘤中表达最频繁的癌症-睾丸抗原。在此，我们通过特异性分析46例膀胱肿瘤和10例正常尿路中MAGE-A3、-A4、-A8和-A9mRNAs，进一步研究了该家族基因的表达。我们发现，它们分别在30%、33%、56%和54%的肿瘤中表达。MAGE-A8虽然是最常见的肿瘤，但其表达水平较低，在大多数正常尿路中也有表达。其他MAGE-A的mRNAs都是肿瘤特异性的，但MAGE-A9mRNA的表达水平较高，且在浅表性肿瘤中的表达频率是侵袭性肿瘤的两倍。为了研究该蛋白的表达，我们制备了两个MAGE-A9特异性的单抗，它们与其他MAGE-A蛋白没有交叉反应。用免疫组织化学方法检测该抗原在睾丸和肿瘤组织中的表达。在睾丸中，MAGE-A9的表达仅限于初级精母细胞。大部分表达MAGE-A9转录本的膀胱肿瘤单抗14A11染色呈阳性，呈异质性，但半数肿瘤的阳性细胞超过75%。最后，我们发现，甲基化抑制剂5-氮杂-2‘-脱氧胞苷单独或与组蛋白脱乙酰酶抑制剂MS-275和4-苯丁酸酯联合处理膀胱癌细胞可以强烈诱导MAGE-A9的表达。这些结果表明MAGE-A9在浅表性膀胱癌中广泛表达，化疗药物可以诱导MAGE-A9的表达，因此MAGE-A9可能成为免疫治疗或化疗免疫治疗的相关靶点。(C)2007年Wiley-Liss，Inc.
In a previous analysis, we showed that MAGE-As were the most frequently expressed cancer-testis antigens in human bladder tumours. Here, we further characterized by RT-PCR the expression of this family of genes by analyzing specifically MAGE-A3, - A4, -A8 and -A9 mRNAs in 46 bladder tumours and 10 normal urothelia. We found that they were expressed in 30, 33, 56 and 54% of tumours, respectively. Although MAGE-A8 was the most frequent, its expression was low and was also found in most normal urothelia. The other MAGE-A mRNAs were all tumour-specific but MAGE-A9 mRNA was expressed at a higher level and was two times more frequent in superficial than in invasive tumours. To study the expression of the protein, we produced 2 MAGE-A9-specific monoclonal antibodies (mAbs) presenting no cross-reactivity with other MAGE-A proteins. MAb 14A11, was used to analyse the expression of the antigen in testis and tumour samples by immunohistochemistry. In testis, MAGE-A9 expression was restricted to primary spermatocytes. Most bladder tumours that expressed the MAGE-A9 transcript were positive with mAb 14A11 Staining was heterogeneous but half of the tumours showed over 75% positive cells. Finally, we showed that treatment of bladder cancer cells with the methylation inhibitor, 5-aza-2'-deoxycytidine, alone or in combination with the histone deacetylase inhibitors MS-275 and 4-phenylbutyrate could strongly induce the expression of MAGE-A9. These results show that MAGE-A9 is frequently expressed in superficial bladder cancer and could be a relevant target for immunotherapy or chemoimmunotherapy because its expression can be induced by chemotherapeutic drugs. (c) 2007 Wiley-Liss, Inc.