Jelena Marjanovic Vicentic1, Danijela Drakulic2, Idoia Garcia3,4,5, Vladanka Vukovic1, Paula Aldaz3,5, Nela Puskas6, Igor Nikolic7,8, Goran Tasic7,8, Savo Raicevic7, Laura Garros-Regulez3, Nicolas Sampron3,5,9, Michael J Atkinson10,11, Natasa Anastasov10, Ander Matheu3,4,5,9, Milena Stevanovic1,12,13. 1. Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. 2. Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia. danijeladrakulic@imgge.bg.ac.rs. 3. Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain. 4. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. 5. CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), Madrid, Spain. 6. Institute of Histology and Embryology "Aleksandar Ð. Kostić", School of Medicine, University of Belgrade, Belgrade, Serbia. 7. Clinical Center of Serbia, Clinic for Neurosurgery, Belgrade, Serbia. 8. Medical Faculty, University of Belgrade, Belgrade, Serbia. 9. Neuro-oncology Tumor Board, Donostia Hospital, San Sebastian, Spain. 10. Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. 11. Chair of Radiation Biology, Technical University of Munich, Munich, Germany. 12. Faculty of Biology, University of Belgrade, Belgrade, Serbia. 13. Serbian Academy of Sciences and Arts, Belgrade, Serbia.
Abstract
PURPOSE: Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma. METHODS: SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively. RESULTS: Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells. CONCLUSION: From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.
PURPOSE: Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma. METHODS: SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively. RESULTS: Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells. CONCLUSION: From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.
Authors: Cameron W Brennan; Roel G W Verhaak; Aaron McKenna; Benito Campos; Houtan Noushmehr; Sofie R Salama; Siyuan Zheng; Debyani Chakravarty; J Zachary Sanborn; Samuel H Berman; Rameen Beroukhim; Brady Bernard; Chang-Jiun Wu; Giannicola Genovese; Ilya Shmulevich; Jill Barnholtz-Sloan; Lihua Zou; Rahulsimham Vegesna; Sachet A Shukla; Giovanni Ciriello; W K Yung; Wei Zhang; Carrie Sougnez; Tom Mikkelsen; Kenneth Aldape; Darell D Bigner; Erwin G Van Meir; Michael Prados; Andrew Sloan; Keith L Black; Jennifer Eschbacher; Gaetano Finocchiaro; William Friedman; David W Andrews; Abhijit Guha; Mary Iacocca; Brian P O'Neill; Greg Foltz; Jerome Myers; Daniel J Weisenberger; Robert Penny; Raju Kucherlapati; Charles M Perou; D Neil Hayes; Richard Gibbs; Marco Marra; Gordon B Mills; Eric Lander; Paul Spellman; Richard Wilson; Chris Sander; John Weinstein; Matthew Meyerson; Stacey Gabriel; Peter W Laird; David Haussler; Gad Getz; Lynda Chin Journal: Cell Date: 2013-10-10 Impact factor: 41.582
Authors: Paul Kleihues; David N Louis; Bernd W Scheithauer; Lucy B Rorke; Guido Reifenberger; Peter C Burger; Webster K Cavenee Journal: J Neuropathol Exp Neurol Date: 2002-03 Impact factor: 3.685
Authors: Mario L Suvà; Esther Rheinbay; Shawn M Gillespie; Anoop P Patel; Hiroaki Wakimoto; Samuel D Rabkin; Nicolo Riggi; Andrew S Chi; Daniel P Cahill; Brian V Nahed; William T Curry; Robert L Martuza; Miguel N Rivera; Nikki Rossetti; Simon Kasif; Samantha Beik; Sabah Kadri; Itay Tirosh; Ivo Wortman; Alex K Shalek; Orit Rozenblatt-Rosen; Aviv Regev; David N Louis; Bradley E Bernstein Journal: Cell Date: 2014-04-10 Impact factor: 41.582
Authors: Justin D Lathia; Stephen C Mack; Erin E Mulkearns-Hubert; Claudia L L Valentim; Jeremy N Rich Journal: Genes Dev Date: 2015-06-15 Impact factor: 11.361
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