RT Journal Article
T1 Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
A1 Jiménez-Vacas, Juan M.
A1 Herrero-Aguayo, Vicente
A1 Montero-Hidalgo, Antonio J.
A1 Gómez-Gómez, Enrique
A1 Fuentes-Fayos, Antonio C.
A1 León-González, Antonio J.
A1 Sáez-Martínez, Prudencio
A1 Alors-Pérez, Emilia
A1 Pedraza-Arévalo, Sergio
A1 González-Serrano, Teresa
A1 Reyes, Oscar
A1 Martínez-López, Ana
A1 Sánchez-Sánchez, Rafael
A1 Ventura, Sebastián
A1 Yubero-Serrano, Elena M.
A1 Requena-Tapia, María J.
A1 Castaño, Justo P.
A1 Gahete, Manuel D.
A1 Luque, Raúl M.
K1 Prostate cancer
K1 Splicing
K1 Spliceosome
K1 SNRNP200
K1 SRSF3
K1 SRRM1
K1 Therapeutic target
K1 Neoplasias de la próstata
K1 Empalmosomas
K1 Andalucía
K1 ARN mensajero
K1 Western blotting
AB 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.
PB Elsevier
YR 2020
FD 2020-01-03
LK http://hdl.handle.net/10668/4392
UL http://hdl.handle.net/10668/4392
LA en
NO Jiménez-Vacas JM, Herrero-Aguayo V, Montero-Hidalgo AJ, Gómez-Gómez E, Fuentes-Fayos AC, León-González AJ, et al. Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer. EBioMedicine. 2020 Jan;51:102547
DS RISalud
RD Apr 5, 2025