Micro-RNA-128 (miRNA-128) down-regulation in glioblastoma targets ARP5 (ANGPTL6), Bmi-1 and E2F-3a, key regulators of brain cell proliferation
Micro-RNA-128 (miRNA-128) down-regulation in glioblastoma targets ARP5 (ANGPTL6), Bmi-1 and E2F-3a, key regulators of brain cell proliferation
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DOI：
10.1007/s11060-009-0077-0
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发表时间：
2010-07-01
影响因子：
3.9
通讯作者：
Lukiw, W. J.
中科院分区：
文献类型：
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作者：
Cui, J. G.;Zhao, Y.;Lukiw, W. J.
高密度miRNA(MiRNA)阵列、荧光报告基因miRNA分析和Northern miRNA斑点杂交分析表明，与年龄匹配的对照组相比，脑丰富的miRNA-128在多形性胶质母细胞瘤(GBM)和GBM细胞系中显著下调。MiRNA-128表达下调与WHO肿瘤分级呈负相关。经生物信息学验证的三个miRNA-128靶点，血管生成素相关生长因子蛋白5(ARP5；ANGPTL6)，促进干细胞更新并抑制已知的与衰老和分化相关的肿瘤抑制基因的表达，BMI-1，以及控制细胞周期进展的关键转录因子E2F-3a，被发现上调。外源miRNA-128作用于CRL-1690和CRL-2610 GBM细胞后，(A)可恢复ARP5(ANGPTL6)、Bmi-1和E2F-3a的表达；(B)显著抑制CRL-1690和CRL-2610细胞的增殖。我们的数据提示，miRNA-128的下调可能通过协同上调ARP5(ANGPTL6)、Bmi-1和E2F-3a，导致未分化的GBM细胞的增殖，从而在胶质瘤和GBM中发挥作用。
High density micro-RNA (miRNA) arrays, fluorescent-reporter miRNA assay and Northern miRNA dot-blot analysis show that a brain-enriched miRNA-128 is significantly down-regulated in glioblastoma multiforme (GBM) and in GBM cell lines when compared to age-matched controls. The down-regulation of miRNA-128 was found to inversely correlate with WHO tumor grade. Three bioinformatics-verified miRNA-128 targets, angiopoietin-related growth factor protein 5 (ARP5; ANGPTL6), a transcription suppressor that promotes stem cell renewal and inhibits the expression of known tumor suppressor genes involved in senescence and differentiation, Bmi-1, and a transcription factor critical for the control of cell-cycle progression, E2F-3a, were found to be up-regulated. Addition of exogenous miRNA-128 to CRL-1690 and CRL-2610 GBM cell lines (a) restored 'homeostatic' ARP5 (ANGPTL6), Bmi-1 and E2F-3a expression, and (b) significantly decreased the proliferation of CRL-1690 and CRL-2610 cell lines. Our data suggests that down-regulation of miRNA-128 may contribute to glioma and GBM, in part, by coordinately up-regulating ARP5 (ANGPTL6), Bmi-1 and E2F-3a, resulting in the proliferation of undifferentiated GBM cells.