Publication: Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.
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Identifiers
Date
2020-07-05
Authors
Fuentes-Fayos, Antonio C
Vazquez-Borrego, Mari C
Jimenez-Vacas, Juan M
Bejarano, Leire
Pedraza-Arevalo, Sergio
L-Lopez, Fernando
Blanco-Acevedo, Cristobal
Sanchez-Sanchez, Rafael
Reyes, Oscar
Ventura, Sebastian
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford University Press
Abstract
Glioblastomas remain the deadliest brain tumour, with a dismal ∼12-16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology.
Description
MeSH Terms
Alternative splicing
Apoptosis
Biomarkers, tumor
Brain neoplasms
Cell movement
Cell proliferation
Gene expression regulation, neoplastic
Gene silencing
Glioblastoma
Humans
Neoplasm invasiveness
Receptor, platelet-derived growth factor beta
Serine-arginine splicing factors
Signal transduction
Survival analysis
Xenograft model antitumor assays
Apoptosis
Biomarkers, tumor
Brain neoplasms
Cell movement
Cell proliferation
Gene expression regulation, neoplastic
Gene silencing
Glioblastoma
Humans
Neoplasm invasiveness
Receptor, platelet-derived growth factor beta
Serine-arginine splicing factors
Signal transduction
Survival analysis
Xenograft model antitumor assays
DeCS Terms
Análisis de supervivencia
Biomarcadores de tumor
Empalme alternativo
Glioblastoma
Invasividad neoplásica
Movimiento celular
Neoplasias encefálicas
Proliferación celular
Biomarcadores de tumor
Empalme alternativo
Glioblastoma
Invasividad neoplásica
Movimiento celular
Neoplasias encefálicas
Proliferación celular
CIE Terms
Keywords
PDGFRB pathway, SRSF3, Antitumour therapy, Glioblastoma, Splicing machinery
Citation
Fuentes-Fayos AC, Vázquez-Borrego MC, Jiménez-Vacas JM, Bejarano L, Pedraza-Arévalo S, L-López F, et al. Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3. Brain. 2020 Dec 5;143(11):3273-3293