Survivin transcript variant 2 drives angiogenesis and malignant progression in proneural gliomas

Abstract

Background: The influence of survivin isoforms on outcome in glioblastoma is poorly understood. We analyzed the dominant anti-apoptotic transcript variants of survivin using expression data and modeled them in vivo to determine their impact on glioma formation and progression.

Methods: Using data from low- and high-grade glioma knowledge bases, we expressed the anti-apoptotic isoforms of survivin (transcript variants 1 and 2) in vivo using the RCAS/Ntv-a model of murine glioma.

Results: In low-grade gliomas, survivin RNA expression was increased in 22 of 167 (13.2%) of cases and was associated with shortened survival (P = .005). Survivin RNA was preferentially expressed in proneural (PN) relative to mesenchymal high-grade gliomas (P < .0001). In proneural gliomas, survivin was expressed in 94 of 141 (67%) of cases and was associated with shorter disease-free survival (P = .04). In a platelet-derived growth factor subunit B-dependent murine model of PN glioma, ectopic expression of variant 1 yielded tumors in 28 of 30 (93%) of mice, of which 25% were high-grade tumors, whereas ectopic expression of variant 2 yielded tumors in 27 of 28 (96%), of which 81% were high-grade tumors (P < .0001). Microvascular proliferation was significantly more prominent (P < .0001), and tumor-free survival was shorter in mice with variant 2 than variant 1-derived tumors (P = .01).

Conclusions: Survivin expression in low-grade gliomas is associated with poor survival and is preferentially expressed in PN gliomas. Compared with variant 1, variant 2 was associated with poorer survival and promoted malignant progression, angiogenesis, and shorter tumor-free survival in the PN murine model. Inhibiting survivin transcript variant 2, rather than variant 1 (the common isoform), may be an effective treatment strategy for glioma.

Keywords: angiogenesis; apoptosis; glioma; survivin.