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

Hdl Handle:
http://hdl.handle.net/10147/239153
Title:
MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2
Authors:
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
Citation:
Molecular Cancer. 2010 Apr 21;9(1):83
Issue Date:
21-Apr-2010
URI:
http://dx.doi.org/10.1186/1476-4598-9-83; http://hdl.handle.net/10147/239153
Abstract:
Abstract 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.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorFoley, Niamh H-
dc.contributor.authorBray, Isabella M-
dc.contributor.authorTivnan, Amanda-
dc.contributor.authorBryan, Kenneth-
dc.contributor.authorMurphy, Derek M-
dc.contributor.authorBuckley, Patrick G-
dc.contributor.authorRyan, Jacqueline-
dc.contributor.authorO'Meara, Anne-
dc.contributor.authorO'Sullivan, Maureen-
dc.contributor.authorStallings, Raymond L-
dc.date.accessioned2012-08-20T11:56:44Z-
dc.date.available2012-08-20T11:56:44Z-
dc.date.issued2010-04-21-
dc.identifier.citationMolecular Cancer. 2010 Apr 21;9(1):83-
dc.identifier.urihttp://dx.doi.org/10.1186/1476-4598-9-83-
dc.identifier.urihttp://hdl.handle.net/10147/239153-
dc.description.abstractAbstract 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.-
dc.titleMicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderNiamh H Foley et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2012-08-20T11:08:09Z-
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