Cargando…

miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression

RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tum...

Descripción completa

Detalles Bibliográficos
Autores principales: Epis, Michael R., Giles, Keith M., Beveridge, Dianne J., Richardson, Kirsty L., Candy, Patrick A., Stuart, Lisa M., Bentel, Jacqueline, Cohen, Ronald J., Leedman, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589646/
https://www.ncbi.nlm.nih.gov/pubmed/28903407
http://dx.doi.org/10.18632/oncotarget.18664
_version_ 1783262374686359552
author Epis, Michael R.
Giles, Keith M.
Beveridge, Dianne J.
Richardson, Kirsty L.
Candy, Patrick A.
Stuart, Lisa M.
Bentel, Jacqueline
Cohen, Ronald J.
Leedman, Peter J.
author_facet Epis, Michael R.
Giles, Keith M.
Beveridge, Dianne J.
Richardson, Kirsty L.
Candy, Patrick A.
Stuart, Lisa M.
Bentel, Jacqueline
Cohen, Ronald J.
Leedman, Peter J.
author_sort Epis, Michael R.
collection PubMed
description RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3’-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa.
format Online
Article
Text
id pubmed-5589646
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-55896462017-09-12 miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression Epis, Michael R. Giles, Keith M. Beveridge, Dianne J. Richardson, Kirsty L. Candy, Patrick A. Stuart, Lisa M. Bentel, Jacqueline Cohen, Ronald J. Leedman, Peter J. Oncotarget Research Paper RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3’-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa. Impact Journals LLC 2017-06-27 /pmc/articles/PMC5589646/ /pubmed/28903407 http://dx.doi.org/10.18632/oncotarget.18664 Text en Copyright: © 2017 Epis et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Epis, Michael R.
Giles, Keith M.
Beveridge, Dianne J.
Richardson, Kirsty L.
Candy, Patrick A.
Stuart, Lisa M.
Bentel, Jacqueline
Cohen, Ronald J.
Leedman, Peter J.
miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title_full miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title_fullStr miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title_full_unstemmed miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title_short miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression
title_sort mir-331-3p and aurora kinase inhibitor ii co-treatment suppresses prostate cancer tumorigenesis and progression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589646/
https://www.ncbi.nlm.nih.gov/pubmed/28903407
http://dx.doi.org/10.18632/oncotarget.18664
work_keys_str_mv AT epismichaelr mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT gileskeithm mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT beveridgediannej mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT richardsonkirstyl mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT candypatricka mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT stuartlisam mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT benteljacqueline mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT cohenronaldj mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression
AT leedmanpeterj mir3313pandaurorakinaseinhibitoriicotreatmentsuppressesprostatecancertumorigenesisandprogression