Expression of MAGE and GAGE genes in medulloblastoma and modulation of resistance to chemotherapy. Laboratory investigation.
OBJECTIVE
Cancer testis antigens (CTAs) were initially identified by their ability to elicit autologous T-cell-mediated immune responses in patients with melanoma. The CTA genes are widely expressed in a variety of human cancers, such as melanoma, breast cancer, lung cancer, esophageal cancer, and hepatocellular carcinoma; however, their expression in pediatric brain tumors, such as medulloblastoma (MB), has not been the subject of in-depth analysis. The MAGE proteins are members of the CTA family and have been shown to correlate with tumor development, aggressive clinical course, or resistance to chemotherapeutic agents. The authors undertook this study to examine the expression and role of MAGE proteins in human MB cell lines and specimens.


METHODS
From a transcriptional profiling study in which 47,000 genes in MB cell lines were examined, the authors identified members of the MAGE and GAGE families as being highly expressed. A series of MB tumors was examined using both immunohistochemistry and Western blot analysis with antibodies to the MAGE-A family, MAGE-A1, and GAGE proteins.


RESULTS
Western blot analysis showed expression of these 3 proteins (MAGE-A family, MAGE-A1, and GAGE) in 62, 46, and 84%, respectively, of MB specimens examined. In addition, a correlation was observed between the expression of MAGE and GAGE genes and resistance of MB cells to chemotherapeutic agents. The functional significance of this correlation was examined in MAGE knockdown studies, and increased drug-induced cytotoxicity was observed in UW426 MB cells following treatment with chemotherapeutic drugs. Cleaved caspase-3 was found in UW426/MAGE small interfering (si)RNA-inhibited cells treated with cisplatin, but not in UW426 cells treated with cisplatin alone at the same concentration.


CONCLUSIONS
These data show that MAGE and GAGE family members are expressed in MB cell lines and specimens, and that inhibition of MAGE and GAGE genes by siRNA increases apoptosis of MB cells and sensitizes them to certain chemotherapeutic agents such as cisplatin and etoposide.
Kasuga
Chinatsu
C
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Ontario, Canada.
Nakahara
Yukiko
Y
Ueda
Shigeo
S
Hawkins
Cynthia
C
Taylor
Michael D
MD
Smith
Christian A
CA
Rutka
James T
JT
D000951:Antigens, Neoplasm / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics*; D058950:Melanoma-Specific Antigens; D046228:Microarray Analysis; D009363:Neoplasm Proteins / Q000235:genetics*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins