Journal Article

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

O'Meara, Anne, O'Sullivan, Maureen, Stallings, Raymond L., Bray, Isabella M., Murphy, Derek M., Ryan, Jacqueline, Foley, Niamh H., Tivnan, Amanda, Bryan, Kenneth, Buckley, Patrick G.

2010

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Apoptosis / Apoptosis - genetics / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Cancer / Cancer Research / Cancer therapies / Care and treatment / Cell adhesion & migration / Cell culture / Cell division / Cell Line, Tumor / Children & youth / Cloning / Enzyme inhibitors / Families & family life / Gene Expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Hospitals / Humans / Kinases / MicroRNA / MicroRNAs - genetics / N-Myc Proto-Oncogene Protein / Neuroblastoma / Neuroblastoma - genetics / Neuroblastoma - metabolism / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Oncogene Proteins - genetics / Oncogene Proteins - metabolism / Oncology / Physiological aspects / Proteins / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / Studies / Transcription factors / Transfection / Tumors