Abstract
Melanoma-associated antigen (MAGE) family genes have been considered as potentially promising targets for anticancer immunotherapy. MAGED4 was originally identified as a glioma-specific antigen. Current knowledge about MAGED4 expression in glioma is only based on mRNA analysis and MAGED4 protein expression has not been elucidated. In the present study, we investigated this point and found that MAGED4 mRNA and protein were absent or very lowly expressed in various normal tissues and glioma cell line SHG44, but overexpressed in glioma cell lines A172,U251,U87-MG as well as glioma tissues, with significant heterogeneity. Furthermore, MAGED4 protein expression was positively correlated with the glioma type and grade. We also found that the expression of MAGED4 inversely correlated with the overall methylation status of the MAGED4 promoter CpG island. Furthermore, when SHG44 and A172 with higher methylation were treated with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) reactivation of MAGED4 mRNA was mediated by significant demethylation in SHG44 instead of A172. However, 5-AZA-CdR treatment had no effect on MAGED4 protein in both SHG44 and A172 cells. In conclusion, MAGED4 is frequently and highly expressed in glioma and is partly regulated by DNA methylation. The results suggest that MAGED4 might be a promising target for glioma immunotherapy combined with 5-AZA-CdR to enhance its expression and eliminate intratumor heterogeneity.
Highlights
Gliomas are the most common malignant tumors in the central nervous system, accounting for approximately 50% of primary brain tumors (Zeybek et al, 2013)
When SHG44 and A172 with higher methylation were treated with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) reactivation of MAGED4 mRNA was mediated by significant demethylation in SHG44 instead of A172
In glioma cell lines tested, MAGED4 mRNA was almost absent in SHG44, whereas highly expressed in others, among which U87-MG exhibited the strongest expression (Figure 1B)
Summary
Gliomas are the most common malignant tumors in the central nervous system, accounting for approximately 50% of primary brain tumors (Zeybek et al, 2013) These tumors are characterized by rapid invasive growth into surrounding brain parenchyma, and result in a poor prognosis, despite advances in surgical resection, radiotherapy and chemotherapy (Ohgaki et al, 2005; Wu et al, 2012). Some immunotherapeutic approaches have been explored as complementary treatments for patients with glioma, but satisfactory antitumor effects were not observed (Yang et al, 2003). This might be partially attributed to the lack of a well-defined glioma-specific antigen
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