2026-04-30T10:28:15Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/181822024-11-29T16:52:52Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Fuentes-Fayos, Antonio C author Vázquez-Borrego, Mari C author Jiménez-Vacas, Juan M author Bejarano, Leire author Pedraza-Arévalo, Sergio author L-López, Fernando author Blanco-Acevedo, Cristóbal author Sánchez-Sánchez, Rafael author Reyes, Oscar author Ventura, Sebastián author Solivera, Juan author Breunig, Joshua J author Blasco, María A author Gahete, Manuel D author Castaño, Justo P author Luque, Raúl M author Blasco, MA author 2020-12-05 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. Brain . 2020 ;143(11):3273-3293. 10.1093/brain/awaa273 1460-2156 Brain : a journal of neurology 33141183 http://hdl.handle.net/20.500.12105/18182 Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.