miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS.
miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS.
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DOI：
10.18632/oncotarget.6968
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发表时间：
2016-04-12
期刊：
影响因子：
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通讯作者：
Condorelli G
中科院分区：
文献类型：
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作者：
Fiore D;Donnarumma E;Roscigno G;Iaboni M;Russo V;Affinito A;Adamo A;De Martino F;Quintavalle C;Romano G;Greco A;Soini Y;Brunetti A;Croce CM;Condorelli G
胶质母细胞瘤是成人中最常见的原发性脑肿瘤;从诊断起生存率为12个月。然而，一小群患者，称为长期存活者（LTS），其存活率超过12-14个月。因此，越来越多的兴趣，在识别的分子标记预测胶质母细胞瘤预后和如何改善治疗方法。在这里，我们报告miR-340作为胶质母细胞瘤的预后肿瘤抑制microRNA。我们分析了> 500例胶质母细胞瘤患者的microRNA表达，发现尽管miR-340在胶质母细胞瘤中总体上强烈下调，但与短期存活者（STS）相比，它在LTS患者中上调。事实上，miR-340表达预测胶质母细胞瘤患者的预后更好。一致地，发现胶质母细胞瘤细胞中miR-340的过表达产生肿瘤抑制活性。我们将NRAS mRNA确定为miR-340的关键直接靶点：事实上，miR-340通过下调NRAS和下游AKT和ERK途径对胶质母细胞瘤肿瘤发生的多个方面产生负面影响。因此，我们证明了胶质母细胞瘤中miR-340的表达通过下调NRAS对LTS患者产生了强烈的肿瘤抑制作用。因此，miR-340可能代表胶质母细胞瘤诊断和预后的新标志物，并可能发展成为改善胶质母细胞瘤治疗的工具。
Glioblastoma is the most common primary brain tumor in adults; with a survival rate of 12 months from diagnosis. However, a small subgroup of patients, termed long-term survivors (LTS), has a survival rate longer then 12–14 months. There is thus increasing interest in the identification of molecular signatures predicting glioblastoma prognosis and in how to improve the therapeutic approach. Here, we report miR-340 as prognostic tumor-suppressor microRNA for glioblastoma. We analyzed microRNA expression in > 500 glioblastoma patients and found that although miR-340 is strongly down-regulated in glioblastoma overall, it is up-regulated in LTS patients compared to short-term survivors (STS). Indeed, miR-340 expression predicted better prognosis in glioblastoma patients. Coherently, overexpression of miR-340 in glioblastoma cells was found to produce a tumor-suppressive activity. We identified NRAS mRNA as a critical, direct target of miR-340: in fact, miR-340 negatively influenced multiple aspects of glioblastoma tumorigenesis by down-regulating NRAS and downstream AKT and ERK pathways. Thus, we demonstrate that expression of miR-340 in glioblastoma is responsible for a strong tumor-suppressive effect in LTS patients by down-regulating NRAS. miR-340 may thus represent a novel marker for glioblastoma diagnosis and prognosis, and may be developed into a tool to improve treatment of glioblastoma.