%0 Journal Article
%A Jiménez-Vacas, Juan M.
%A Herrero-Aguayo, Vicente
%A Montero-Hidalgo, Antonio J.
%A Gómez-Gómez, Enrique
%A Fuentes-Fayos, Antonio C.
%A León-González, Antonio J.
%A Sáez-Martínez, Prudencio
%A Alors-Pérez, Emilia
%A Pedraza-Arévalo, Sergio
%A González-Serrano, Teresa
%A Reyes, Oscar
%A Martínez-López, Ana
%A Sánchez-Sánchez, Rafael
%A Ventura, Sebastián
%A Yubero-Serrano, Elena M.
%A Requena-Tapia, María J.
%A Castaño, Justo P.
%A Gahete, Manuel D.
%A Luque, Raúl M.
%T Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
%D 2020
%U http://hdl.handle.net/10668/4392
%X Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinicallylocalized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, TStage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/ DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC.
%K Prostate cancer
%K Splicing
%K Spliceosome
%K SNRNP200
%K SRSF3
%K SRRM1
%K Therapeutic target
%K Neoplasias de la próstata
%K Empalmosomas
%K Andalucía
%K ARN mensajero
%K Western blotting
%~