Guillermo Aldave1, Marisol Gonzalez-Huarriz2,3,4, Angel Rubio5, Juan Pablo Romero5, Datta Ravi5, Belén Miñana6, Mar Cuadrado-Tejedor3,7,8, Ana García-Osta3,7, Roeland Verhaak9,10, Enric Xipell2,3,4, Naiara Martinez-Vélez2,3,4, Arlet Acanda de la Rocha2,3,4, Montserrat Puigdelloses2,3,4, Marc García-Moure2,3,4, Miguel Marigil2,3,4, Jaime Gállego Pérez-Larraya2,3,4, Oskar Marín-Bejar3,11, Maite Huarte3,11, Maria Stella Carro12, Roberto Ferrarese12, Cristobal Belda-Iniesta13, Angel Ayuso13,14, Ricardo Prat-Acín15, Fernando Pastor3,16, Ricardo Díez-Valle3,4,17, Sonia Tejada3,4,17, Marta M Alonso2,3,4. 1. Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA. 2. Department of Pediatrics, University Hospital of Navarra, Pamplona, Navarra, Spain. 3. Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain. 4. Program in Solid Tumors, Foundation for Applied Medical Research, Pamplona, Navarra, Spain. 5. CEIT and TECNUN, University of Navarra, San Sebastian, Spain. 6. Centre de Regulació Genòmica (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain, Universitat Pompeu-Fabra, Barcelona, Spain. 7. Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. 8. Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain. 9. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 10. Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 11. Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. 12. Department of Neurosurgery (Neurocenter) Universitätsklinikum Freiburg, Freiburg, Germany. 13. Fundación de Investigación HM Hospitales, Grupo HM, Spain. 14. Facultad de Medicina, Universidad CEU-San Pablo, Madrid, Spain. 15. Department of Neurosurgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain. 16. Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Médica Aplicada, Pamplona, Spain. 17. Department of Neurosurgery, University Hospital of Navarra, Pamplona, Navarra, Spain.
Abstract
Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.
Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results:BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.
Authors: W Stummer; S Stocker; S Wagner; H Stepp; C Fritsch; C Goetz; A E Goetz; R Kiefmann; H J Reulen Journal: Neurosurgery Date: 1998-03 Impact factor: 4.654
Authors: Roberto Ferrarese; Griffith R Harsh; Ajay K Yadav; Eva Bug; Daniel Maticzka; Wilfried Reichardt; Stephen M Dombrowski; Tyler E Miller; Anie P Masilamani; Fangping Dai; Hyunsoo Kim; Michael Hadler; Denise M Scholtens; Irene L Y Yu; Jürgen Beck; Vinodh Srinivasasainagendra; Fabrizio Costa; Nicoleta Baxan; Dietmar Pfeifer; Dominik von Elverfeldt; Rolf Backofen; Astrid Weyerbrock; Christine W Duarte; Xiaolin He; Marco Prinz; James P Chandler; Hannes Vogel; Arnab Chakravarti; Jeremy N Rich; Maria S Carro; Markus Bredel Journal: J Clin Invest Date: 2014-05-27 Impact factor: 14.808
Authors: Julie Lessard; Jiang I Wu; Jeffrey A Ranish; Mimi Wan; Monte M Winslow; Brett T Staahl; Hai Wu; Ruedi Aebersold; Isabella A Graef; Gerald R Crabtree Journal: Neuron Date: 2007-07-19 Impact factor: 17.173
Authors: Ahmed Sadeque; Nicola Vl Serão; Bruce R Southey; Kristin R Delfino; Sandra L Rodriguez-Zas Journal: BMC Med Genomics Date: 2012-12-04 Impact factor: 3.063