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Jiménez-Vacas, Juan M.; Herrero-Aguayo, Vicente; Montero-Hidalgo, Antonio J.; Gómez-Gómez, Enrique; Fuentes-Fayos, Antonio C.; León-González, Antonio J.; Sáez-Martínez, Prudencio; Alors-Pérez, Emilia; Pedraza-Arévalo, Sergio; González-Serrano, Teresa; Reyes, Oscar; Martínez-López, Ana; Sánchez-Sánchez, Rafael; Ventura, Sebastián; Yubero-Serrano, Elena M.; Requena-Tapia, María J.; Castaño, Justo P.; Gahete, Manuel D.; Luque, Raúl M.
EBioMedicine, 01/2020, Letnik: 51Journal Article
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. Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). 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, T-Stage, 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). 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.
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