Analysis of the inhibitors of apoptosis identifies BIRC3 as a facilitator of malignant progression in glioma

// Loyola V. Gressot 1 , Tiffany Doucette 1 , Yuhui Yang 1 , Gregory N. Fuller 2 , Ganiraju Manyam 3 , Arvind Rao 3 , Khatri Latha 1 , Ganesh Rao 1 1 Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Correspondence to: Khatri Latha, e-mail: klatha@mdanderson.org Ganesh Rao, e-mail: grao@mdanderson.org Keywords: inhibitor of apoptosis, BIRC3, glioma, malignant progression Received: December 23, 2015      Accepted: March 28, 2016      Published: April 8, 2016 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.