title: 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.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Tiffany
authors.initials: T
authors.lastname: Doucette
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Khatri
authors.initials: K
authors.lastname: Latha
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Arvind
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (T.D., L.K., Y.Y., G.R.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.N.F.); Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.R.).
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality; D016208:Databases, Factual; D018450:Disease Progression; D005910:Glioma / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic; D020033:Protein Isoforms / Q000378:metabolism; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D020033:Protein Isoforms; D000077022:Survivin
keywords: angiogenesis; apoptosis; glioma; survivin