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Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide

Most forms of castration-resistant prostate cancer (CRPC) are dependent on the androgen receptor (AR) for survival. While, enzalutamide provides a substantial survival benefit, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can devel...

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Autores principales: Greene, John, Baird, Anne-Marie, Casey, Orla, Brady, Lauren, Blackshields, Gordon, Lim, Marvin, O’Brien, Odharnaith, Gray, Steven G., McDermott, Raymond, Finn, Stephen P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656767/
https://www.ncbi.nlm.nih.gov/pubmed/31341219
http://dx.doi.org/10.1038/s41598-019-47189-2
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author Greene, John
Baird, Anne-Marie
Casey, Orla
Brady, Lauren
Blackshields, Gordon
Lim, Marvin
O’Brien, Odharnaith
Gray, Steven G.
McDermott, Raymond
Finn, Stephen P.
author_facet Greene, John
Baird, Anne-Marie
Casey, Orla
Brady, Lauren
Blackshields, Gordon
Lim, Marvin
O’Brien, Odharnaith
Gray, Steven G.
McDermott, Raymond
Finn, Stephen P.
author_sort Greene, John
collection PubMed
description Most forms of castration-resistant prostate cancer (CRPC) are dependent on the androgen receptor (AR) for survival. While, enzalutamide provides a substantial survival benefit, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can develop through a number of mechanisms, such as AR copy number gain, the generation of splice variants such as AR-V7 and mutations within the ligand binding domain (LBD) of the AR. circular RNAs (circRNAs) are a novel type of non-coding RNA, which can regulate the function of miRNA, and may play a key role in the development of drug resistance. circRNAs are highly resistant to degradation, are detectable in plasma and, therefore may serve a role as clinical biomarkers. In this study, AR-V7 expression was assessed in an isogenic model of enzalutamide resistance. The model consisted of age matched control cells and two sub-line clones displaying varied resistance to enzalutamide. circRNA profiling was performed on the panel using a high throughout microarray assay. Bioinformatic analysis identified a number of differentially expressed circRNAs and predicted five miRNA binding sites for each circRNA. miRNAs were stratified based on known associations with prostate cancer, and targets were validated using qPCR. Overall, circRNAs were more often down regulated in resistant cell lines compared with control (588 vs. 278). Of particular interest was hsa_circ_0004870, which was down-regulated in enzalutamide resistant cells (p ≤ 0.05, vs. sensitive cells), decreased in cells that highly express AR (p ≤ 0.01, vs. AR negative), and decreased in malignant cells (p ≤ 0.01, vs. benign). The associated parental gene was identified as RBM39, a member of the U2AF65 family of proteins. Both genes were down-regulated in resistant cells (p < 0.05, vs. sensitive cells). This is one of the first studies to profile and demonstrate discrete circRNA expression patterns in an enzalutamide resistant cell line model of prostate cancer. Our data suggests that hsa_circ_0004870, through RBM39, may play a critical role in the development of enzalutamide resistance in CRPC.
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spelling pubmed-66567672019-07-29 Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide Greene, John Baird, Anne-Marie Casey, Orla Brady, Lauren Blackshields, Gordon Lim, Marvin O’Brien, Odharnaith Gray, Steven G. McDermott, Raymond Finn, Stephen P. Sci Rep Article Most forms of castration-resistant prostate cancer (CRPC) are dependent on the androgen receptor (AR) for survival. While, enzalutamide provides a substantial survival benefit, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can develop through a number of mechanisms, such as AR copy number gain, the generation of splice variants such as AR-V7 and mutations within the ligand binding domain (LBD) of the AR. circular RNAs (circRNAs) are a novel type of non-coding RNA, which can regulate the function of miRNA, and may play a key role in the development of drug resistance. circRNAs are highly resistant to degradation, are detectable in plasma and, therefore may serve a role as clinical biomarkers. In this study, AR-V7 expression was assessed in an isogenic model of enzalutamide resistance. The model consisted of age matched control cells and two sub-line clones displaying varied resistance to enzalutamide. circRNA profiling was performed on the panel using a high throughout microarray assay. Bioinformatic analysis identified a number of differentially expressed circRNAs and predicted five miRNA binding sites for each circRNA. miRNAs were stratified based on known associations with prostate cancer, and targets were validated using qPCR. Overall, circRNAs were more often down regulated in resistant cell lines compared with control (588 vs. 278). Of particular interest was hsa_circ_0004870, which was down-regulated in enzalutamide resistant cells (p ≤ 0.05, vs. sensitive cells), decreased in cells that highly express AR (p ≤ 0.01, vs. AR negative), and decreased in malignant cells (p ≤ 0.01, vs. benign). The associated parental gene was identified as RBM39, a member of the U2AF65 family of proteins. Both genes were down-regulated in resistant cells (p < 0.05, vs. sensitive cells). This is one of the first studies to profile and demonstrate discrete circRNA expression patterns in an enzalutamide resistant cell line model of prostate cancer. Our data suggests that hsa_circ_0004870, through RBM39, may play a critical role in the development of enzalutamide resistance in CRPC. Nature Publishing Group UK 2019-07-24 /pmc/articles/PMC6656767/ /pubmed/31341219 http://dx.doi.org/10.1038/s41598-019-47189-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Greene, John
Baird, Anne-Marie
Casey, Orla
Brady, Lauren
Blackshields, Gordon
Lim, Marvin
O’Brien, Odharnaith
Gray, Steven G.
McDermott, Raymond
Finn, Stephen P.
Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title_full Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title_fullStr Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title_full_unstemmed Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title_short Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
title_sort circular rnas are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656767/
https://www.ncbi.nlm.nih.gov/pubmed/31341219
http://dx.doi.org/10.1038/s41598-019-47189-2
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