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

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.

Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide

“…A recent study suggested that cIAP-2 (also known as BIRC3) is a novel driver of therapeutic resistance and is associated with aggressiveness in GBM patients ( 53 ). cIAP-2 has also been identified as a key facilitator of malignant transformation of low-grade gliomas to high-grade gliomas ( 54 ). Bcl-2 and other members of anti-apoptotic proteins (cIAP-1, XIAP and Survivin) can disrupt the activation of caspases and block the progression of apoptosis.…”

Identification of microRNA-124 in regulation of Hepatocellular carcinoma through BIRC3 and the NF-κB pathway

“…It has been reported that BIRC3 was involved in multiple biological processes, including cell proliferation, migration and apoptosis 27 , and high expression of BIRC3 was found in variety of human malignant tumors 28 . For example, Gressot 29 et al reported that BIRC3 accelerated malignant transformation of low-grade gliomas (LGG) to high-grade gliomas (HGG) as a facilitator of malignant progression in glioma. Wang 30 et al found that up-regulation of BIRC3 resulted in apoptosis evasion and therapeutic resistance in glioblastoma both in vivo and in vitro .…”

NO-Donor Nitrosyl Iron Complex with 2-Aminophenolyl Ligand Induces Apoptosis and Inhibits NF-κB Function in HeLa Cells

“…Since both NO and NF-κB play different (and often opposite) roles in the functions of the cell, we studied representative genes belonging to two groups with very different functions: Unrelated to apoptosis cytokine genes IL6 and IL8, and closely related to apoptosis IAPs family genes BIRC2 and BIRC3. Like many other NF-κB target genes, IL6, IL8, BIRC2 and BIRC3 are related to tumor progression and treatment: cytokines are involved into regulation of tumor microenvironment [91][92][93], whereas IAPs contribute to tumor cell survival [94][95][96][97][98]. The observed 2-AmPh-induced suppression of IL8 gene expression demonstrates that NO delivery to tumor cells might be beneficial for interfering with tumor promoting microenvironment conditions, e.g., angiogenesis [91].…”