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Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

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 mo...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000340/
https://www.ncbi.nlm.nih.gov/pubmed/31902674
http://dx.doi.org/10.1016/j.ebiom.2019.11.008
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author 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.
author_facet 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.
author_sort Jiménez-Vacas, Juan M.
collection PubMed
description 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) Clinically-localized 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, 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). 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.
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spelling pubmed-70003402020-02-10 Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer 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 Research paper 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) Clinically-localized 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, 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). 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. Elsevier 2020-01-03 /pmc/articles/PMC7000340/ /pubmed/31902674 http://dx.doi.org/10.1016/j.ebiom.2019.11.008 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
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.
Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title_full Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title_fullStr Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title_full_unstemmed Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title_short Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
title_sort dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000340/
https://www.ncbi.nlm.nih.gov/pubmed/31902674
http://dx.doi.org/10.1016/j.ebiom.2019.11.008
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