High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas

Abstract

Despite recent advances in the understanding of high-grade gliomas, they are among the most malignant of all cancers, with dismal patient outcomes. The classification of gliomas follows the World Health Organization (WHO) classification, which is based on knowledge of cytologic features and degrees of malignancy. The most aggressive form of glioma, the glioblastoma (GBM), represents 29% of primary brain tumors and about 55% of all gliomas 1,2,3 . In spite of standard treatment with surgery, chemotherapy with temozolomide, and radiotherapy, glioblastomas are always fatal with a median survival rate of less than a year and a five-year survival rate of less than 10% of the cases 4,5,6,7 . The glioblastomas are characterized by complex heterogeneity. A new definition of this heterogeneity was recently proposed based on genomic, transcriptomic and epigenomic studies carried out by The Cancer Genome Atlas Network. Through the latter's analyses, the GBMs were clustered into four subgroups: proneural, neural, classical and mesenchymal, which correlate with biological properties of the tumors and measures of clinical outcome 8,9 . ABSTRACT Glioblastoma (GBM) is the most malignant glioma and represents 29% of all brain tumors. Tumorigenesis is intimately connected with characteristics acquired in the physiologic pathway of cellular death. Objective: In the present study, the expression of anti-apoptotic (XIAP and Bcl-2) and apoptotic (cytochrome C, caspase 9, APAF-1), caspase 3 and the Smac/DIABLO genes related to the apoptosis pathway were evaluated in 30 samples of glioblastoma. Methods: The gene expression was evaluated in 30 glioblastomas (WHO grade IV) and compared to 10 white matter control samples with real-time PCR. Results and Conclusion: There were higher expressions of XIAP (p = 0.0032) and Bcl-2 (p = 0.0351) in the glioblastoma samples compared to the control samples of normal brain. These results raise the question of whether Bcl-2 and XIAP genes can be responsible for the inhibition of programmed cell death in glioblastomas. Moreover, they provide additional information capable of allowing the development of new target therapy strategies.Keywords: glioblastoma; apoptosis; X-linked inhibitor of apoptosis protein; B-cell lymphoma 2. RESUMOO glioblastoma (GBM) é o glioma mais maligno e representa 29% de todos os tumores cerebrais. A tumorigênese está intimamente ligada à características adquiridas na via fisiológica de morte celular. Objetivo: Avaliar a expressão de genes anti-apoptóticos (XIAP e Bcl-2) e apoptóticos (citocromo C, a caspase 9, APAF-1), caspase 3 e SMAC/DIABLO, relacionados à apoptose, em 30 amostras de tecido de pacientes com glioblastoma. Métodos: A expressão gênica foi avaliada em trinta glioblastomas e comparada a dez amostras controles de substância branca por PCR em tempo real. Resultados e Conclusão: Houve maior nível de expressão de XIAP (p = 0,0032) e Bcl-2 (p = 0,0351) em comparação com as amostras controle, de cérebro normal. Estes resultados levantam a questão de que os genes Bcl-2 e...

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