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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-7000340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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