microRNA Signature and Expression of Dicer and Drosha Can Predict Prognosis and Delineate Risk Groups in Neuroblastoma
microRNA Signature and Expression of Dicer and Drosha Can Predict Prognosis and Delineate Risk Groups in Neuroblastoma
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DOI：
10.1158/0008-5472.can-10-0970
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Alice L.
中科院分区：
文献类型：
--
作者：
Lin, Ruey-Jen;Lin, You-Chin;Yu, Alice L.
神经母细胞瘤是一种常见的儿童肿瘤，占儿童癌症死亡病例的15%。为了研究微小RNA（miRNA）图谱以及Dicer和Drosha在神经母细胞瘤中的作用，我们采用实时聚合酶链反应（PCR）方法评估了162种人类miRNA、Dicer和Drosha在66例神经母细胞瘤中的表达情况。我们发现晚期神经母细胞瘤中miRNA表达整体下调，并确定了27种能够明确区分低风险和高风险患者的miRNA。此外，Dicer或Drosha在高风险神经母细胞瘤中的表达水平较低，这解释了晚期疾病中miRNA的整体下调，并与不良预后相关。值得注意的是，对于非MYCN扩增肿瘤患者，Dicer的低表达可作为不良预后的一个显著且独立的预测因子（风险比为9.6；P = 0.045；n = 52）。利用合理的神经网络选择由12种miRNA特征、Dicer和Drosha的表达水平以及诊断时年龄组成的15种生物标志物组合，我们能够将所有患者分为四种不同的模式，这些模式对临床预后具有高度预测性。体外研究还表明，敲低Dicer或Drosha可促进神经母细胞瘤细胞系的生长。我们的研究结果显示，15种生物标志物的组合能够描绘神经母细胞瘤的风险组，并作为临床预后的有力预测因子。此外，我们通过沉默Dicer/Drosha促进生长的发现暗示它们有可能作为神经母细胞瘤的治疗靶点。《癌症研究》；70(20)；7841 - 50。（C）2010美国癌症研究协会。
Neuroblastoma is a common childhood tumor and accounts for 15% of pediatric cancer deaths. To investigate the microRNA (miRNA) profile and role of Dicer and Drosha in neuroblastoma, we assessed the expression of 162 human miRNAs, Dicer and Drosha in 66 neuroblastoma tumors by using real-time PCR methods. We found global downregulation of miRNA expression in advanced neuroblastoma and identified 27 miRNAs that can clearly distinguish low-from high-risk patients. Furthermore, expression levels of Dicer or Drosha were low in high-risk neuroblastoma tumors, which accounted for global downregulation of miRNAs in advanced disease and correlated with poor outcome. Notably, for patients with non-MYCN-amplified tumors, low expression of Dicer can serve as a significant and independent predictor of poor outcome (hazard ratio, 9.6; P = 0.045; n = 52). Using plausible neural networks to select a combination of 15 biomarkers that consist of 12 miRNAs' signature, expression levels of Dicer and Drosha, and age at diagnosis, we were able to segregate all patients into four distinct patterns that were highly predictive of clinical outcome. In vitro studies also showed that knockdown of either Dicer or Drosha promoted the growth of neuroblastoma cell lines. Our results reveal that a combination of 15 biomarkers can delineate risk groups of neuroblastoma and serve as a powerful predictor of clinical outcome. Moreover, our findings of growth promotion by silencing Dicer/Drosha implied their potential use as therapeutic targets for neuroblastoma. Cancer Res; 70(20); 7841-50. (C) 2010 AACR.