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

Background. The influence of survivin isoforms on outcome in glioblastoma is poorly understood. We analyzed the dominant antiapoptotic 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 ¼ .005). Survivin RNAwas 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 ¼ .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 ¼ .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.