MAGE-A9 mRNA and protein expression in bladder cancer.
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.
Picard
Valérie
V
Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, 10 McMahon, Québec City, Québec, Canada.
Bergeron
Alain
A
Larue
Hélène
H
Fradet
Yves
Y
D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077209:Decitabine; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D010654:Phenylbutyrates / Q000494:pharmacology; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D013736:Testicular Neoplasms / Q000235:genetics / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; C520253:MAGEA9 protein, human; D009363:Neoplasm Proteins; D010654:Phenylbutyrates; D020033:Protein Isoforms; D011725:Pyridines; D012333:RNA, Messenger; C118739:entinostat; D000077209:Decitabine; C075773:4-phenylbutyric acid; D001374:Azacitidine