Abstract
Gliomas, the most common primary brain tumor in humans, include a spectrum of disease. High-grade gliomas (HGG), such as glioblastoma, may arise from low-grade gliomas (LGG) that have a more indolent course. The process of malignant transformation (MT) of LGG to HGG is poorly understood but likely involves the activation of signaling programs that suppress apoptosis. We previously showed that Survivin (BIRC5) plays a role in malignant progression of glioma. Here, we investigated the role of the remaining members of the Inhibitors of Apoptosis (IAP) family on promoting MT in glioma. Utilizing expression data from the cancer genome atlas (TCGA), we identified BIRC3 as a key facilitator of MT from LGG to HGG. TCGA HGGs with high expression of BIRC 3 demonstrated a survival disadvantage and expression levels of BIRC3 were also significantly higher in TCGA HGG compared to TCGA LGG cases. We validated our findings from TCGA by using matched human specimens to show that BIRC expression is increased in HGG compared to their precursor LGG lesions. Using a unique murine model of glioma, we show that overexpression of BIRC3 promotes higher grade glioma and significantly reduces tumor-free survival in mice.
Highlights
Glioblastoma (GB), the most common primary malignant brain tumor in humans has a 5-year survival rate of only 10% despite aggressive treatment [1]
BIRC3 is highly differentially expressed in High-grade gliomas (HGG) compared to lowgrade gliomas (LGG)
BIRC3 expression is associated with shorter survival in LGG and GB patients
Summary
Glioblastoma (GB), the most common primary malignant brain tumor in humans has a 5-year survival rate of only 10% despite aggressive treatment [1]. LGGs often have an indolent clinical course until they progress to high-grade gliomas (HGGs) such as GB, after which survival time decreases significantly. The causes of this malignant progression are largely unknown. IAPs are a family of eight anti-apoptotic proteins whose overexpression has been linked to numerous malignancies including gliomas [6]. This family of 8 human proteins is characterized by a conserved baculoviral IAP repeat (BIR). Elucidating factors that facilitate www.impactjournals.com/oncotarget the progression of gliomas and clarifying the role that IAPs play in this process is critical as mitigating their activity offers an opportunity for therapeutic intervention
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