MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2.
MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2.
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DOI：
10.1186/1476-4598-9-83
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发表时间：
2010-04-21
期刊：
影响因子：
37.3
通讯作者：
Stallings RL
中科院分区：
文献类型：
--
作者：
Foley NH;Bray IM;Tivnan A;Bryan K;Murphy DM;Buckley PG;Ryan J;O'Meara A;O'Sullivan M;Stallings RL
神经母细胞瘤是一种儿童交感神经系统癌症。不良临床结果的最重要的遗传指标是MYCN转录因子的扩增。MYCN的众多下游靶点之一是miR-184， miR-184直接或间接受到该转录因子的抑制，可能是由于其在神经母细胞瘤细胞中异位过表达时的促凋亡作用。本研究的目的是阐明miR-184表达促凋亡作用的分子机制。我们证明，内源性miR-184的敲低具有与异位上调相反的作用，导致神经母细胞瘤细胞数量增加。作为miR-184在过度表达时导致细胞凋亡和抑制时细胞数量增加的机制，我们证明了直接靶向和降解AKT2，这是磷脂酰肌醇3-激酶（PI3K）途径的主要下游效应物，是癌症中最有效的促生存途径之一。miR-184异位过表达在神经母细胞瘤细胞系中的促凋亡作用是通过siRNA抑制AKT2来实现的，而通过AKT2的异位上调可以实现与内源性miR-184敲低类似的对细胞数量的积极影响。此外，将miR-184与3'UTR中缺乏miR-184靶点的AKT2表达载体共转染，可使细胞免受miR-184的促凋亡作用。MYCN通过抑制miR-184促进肿瘤发生，导致AKT2水平升高，AKT2是miR-184的直接靶点。因此，两个对细胞生长和存活有积极影响的重要基因MYCN和AKT2可以通过miR-184的作用连接到一个共同的遗传通路上。作为AKT2的抑制剂，miR-184可能在miRNA介导的MYCN扩增神经母细胞瘤和其他形式癌症的治疗中具有潜在的益处。
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. 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. 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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影响因子：
64.8
作者：
Hatfield, SD;Shcherbata, HR;Ruohola-Baker, H
通讯作者：
Ruohola-Baker, H
影响因子：
10.3
作者：
Chayka, Olesya;Corvetta, Daisy;Sala, Arturo
通讯作者：
Sala, Arturo
影响因子：
3.7
作者：
Bray I;Bryan K;Prenter S;Buckley PG;Foley NH;Murphy DM;Alcock L;Mestdagh P;Vandesompele J;Speleman F;London WB;McGrady PW;Higgins DG;O'Meara A;O'Sullivan M;Stallings RL
通讯作者：
Stallings RL
影响因子：
56.9
作者：
BRODEUR, GM;SEEGER, RC;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
5.2
作者：
Cole, Kristina A.;Attiyeh, Edward F.;Maris, John M.
通讯作者：
Maris, John M.