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MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

BACKGROUND: Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly represse...

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Autores principales: Foley, Niamh H, Bray, Isabella M, Tivnan, Amanda, Bryan, Kenneth, Murphy, Derek M, Buckley, Patrick G, Ryan, Jacqueline, O'Meara, Anne, O'Sullivan, Maureen, Stallings, Raymond L
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864218/
https://www.ncbi.nlm.nih.gov/pubmed/20409325
http://dx.doi.org/10.1186/1476-4598-9-83
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author Foley, Niamh H
Bray, Isabella M
Tivnan, Amanda
Bryan, Kenneth
Murphy, Derek M
Buckley, Patrick G
Ryan, Jacqueline
O'Meara, Anne
O'Sullivan, Maureen
Stallings, Raymond L
author_facet Foley, Niamh H
Bray, Isabella M
Tivnan, Amanda
Bryan, Kenneth
Murphy, Derek M
Buckley, Patrick G
Ryan, Jacqueline
O'Meara, Anne
O'Sullivan, Maureen
Stallings, Raymond L
author_sort Foley, Niamh H
collection PubMed
description BACKGROUND: Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects. RESULTS: We demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects of miR-184 ectopic over-expression in neuroblastoma cell lines is reproduced by siRNA inhibition of AKT2, while a positive effect on cell numbers similar to that obtained by the knock-down of endogenous miR-184 can be achieved by ectopic up-regulation of AKT2. Moreover, co-transfection of miR-184 with an AKT2 expression vector lacking the miR-184 target site in the 3'UTR rescues cells from the pro-apoptotic effects of miR-184. CONCLUSIONS: MYCN contributes to tumorigenesis, in part, by repressing miR-184, leading to increased levels of AKT2, a direct target of miR-184. Thus, two important genes with positive effects on cell growth and survival, MYCN and AKT2, can be linked into a common genetic pathway through the actions of miR-184. As an inhibitor of AKT2, miR-184 could be of potential benefit in miRNA mediated therapeutics of MYCN amplified neuroblastoma and other forms of cancer.
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spelling pubmed-28642182010-05-05 MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2 Foley, Niamh H Bray, Isabella M Tivnan, Amanda Bryan, Kenneth Murphy, Derek M Buckley, Patrick G Ryan, Jacqueline O'Meara, Anne O'Sullivan, Maureen Stallings, Raymond L Mol Cancer Research BACKGROUND: Neuroblastoma is a paediatric cancer of the sympathetic nervous system. The single most important genetic indicator of poor clinical outcome is amplification of the MYCN transcription factor. One of many down-stream MYCN targets is miR-184, which is either directly or indirectly repressed by this transcription factor, possibly due to its pro-apoptotic effects when ectopically over-expressed in neuroblastoma cells. The purpose of this study was to elucidate the molecular mechanism by which miR-184 conveys pro-apoptotic effects. RESULTS: We demonstrate that the knock-down of endogenous miR-184 has the opposite effect of ectopic up-regulation, leading to enhanced neuroblastoma cell numbers. As a mechanism of how miR-184 causes apoptosis when over-expressed, and increased cell numbers when inhibited, we demonstrate direct targeting and degradation of AKT2, a major downstream effector of the phosphatidylinositol 3-kinase (PI3K) pathway, one of the most potent pro-survival pathways in cancer. The pro-apoptotic effects of miR-184 ectopic over-expression in neuroblastoma cell lines is reproduced by siRNA inhibition of AKT2, while a positive effect on cell numbers similar to that obtained by the knock-down of endogenous miR-184 can be achieved by ectopic up-regulation of AKT2. Moreover, co-transfection of miR-184 with an AKT2 expression vector lacking the miR-184 target site in the 3'UTR rescues cells from the pro-apoptotic effects of miR-184. CONCLUSIONS: MYCN contributes to tumorigenesis, in part, by repressing miR-184, leading to increased levels of AKT2, a direct target of miR-184. Thus, two important genes with positive effects on cell growth and survival, MYCN and AKT2, can be linked into a common genetic pathway through the actions of miR-184. As an inhibitor of AKT2, miR-184 could be of potential benefit in miRNA mediated therapeutics of MYCN amplified neuroblastoma and other forms of cancer. BioMed Central 2010-04-21 /pmc/articles/PMC2864218/ /pubmed/20409325 http://dx.doi.org/10.1186/1476-4598-9-83 Text en Copyright ©2010 Foley et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Foley, Niamh H
Bray, Isabella M
Tivnan, Amanda
Bryan, Kenneth
Murphy, Derek M
Buckley, Patrick G
Ryan, Jacqueline
O'Meara, Anne
O'Sullivan, Maureen
Stallings, Raymond L
MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title_full MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title_fullStr MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title_full_unstemmed MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title_short MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
title_sort microrna-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase akt2
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864218/
https://www.ncbi.nlm.nih.gov/pubmed/20409325
http://dx.doi.org/10.1186/1476-4598-9-83
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