Micro RNA Profiling in Pediatric Cancers

目的：microRNA已被证明与不同的人类癌症有关。因此，我们对一组儿童肿瘤进行了表达谱分析，以确定癌症特异性microRNA，我们还研究了microRNA是否与其宿主基因共同调控。实验设计：我们使用微阵列对代表10种不同儿科实体瘤的57种肿瘤异种移植物和细胞系进行了平行的microRNA和mRNA表达谱分析。对于那些映射到其宿主mRNA的microRNA，我们计算了它们之间的相关性。结果：我们发现，大多数癌症类型聚集在一起，基于其全球microRNA表达谱的无监督层次聚类。14种microRNA在横纹肌肉瘤和神经母细胞瘤中有显著差异表达，其中8种在独立的患者肿瘤样本中得到验证。对microRNA表达与宿主基因关系的探索表明，位于已知编码基因内的68个microRNA中有43个（63%）的表达与其宿主基因的表达显著相关。在这43个microRNA中，OncomiR-1簇中的7个microRNA中的5个与其宿主基因MIRHG 1显著相关（P 0.01）。此外，MIRHG 1的高表达与神经母细胞瘤肿瘤的高分期和MYCN扩增显著相关，MIRHG 1的表达水平可以独立于两个独立患者队列中当前神经母细胞瘤风险分层来预测神经母细胞瘤患者的结局。OncomiR-1宿主基因MIRHG 1的高表达与神经母细胞瘤患者的不良结局相关，表明该microRNA簇在神经母细胞瘤生物学中具有重要的致癌功能。(Clin Cancer Res 2009;15（17）：55608）

Purpose: microRNAs have been shown to be involved in different human cancers. We therefore have performed expression profiles on a panel of pediatric tumors to identify cancerspecific microRNAs.We also investigated if microRNAs are coregulated with their host gene. Experimental Design: We performed parallel microRNAs and mRNA expression profiling on 57 tumor xenografts and cell lines representing 10 different pediatric solid tumors using microarrays. For those microRNAs that map to their host mRNA, wecalculated correlations between them.Results: We found that the majority of cancer types clustered together based on their global microRNA expression profiles by unsupervised hierarchical clustering. Fourteen microRNAs were significantly differentially expressed between rhabdomyosarcoma and neuroblastoma, and 8 of them were validated in independent patient tumor samples. Exploration of the expression of microRNAs in relationship with their host genes showed that the expression for 43 of 68 (63%) microRNAs located inside known coding genes was significantly correlated with that of their host genes. Among these 43 microRNAs, 5 of 7 microRNAs in the OncomiR-1 cluster correlated significantly with their host gene MIRHG1 (P < 0.01). In addition, high expression of MIRHG1 was significantly associated with high stage and MYCN amplification in neuroblastoma tumors, and the expression level of MIRHG1 could predict the outcome of neuroblastoma patients independently from the current neuroblastoma risk-stratification in two independent patient cohorts.Conclusion: Pediatric cancers express cancer-specific microRNAs. The high expression of the OncomiR-1 host gene MIRHG1 correlates with poor outcome for patients with neuroblastoma, indicating important oncogenic functions of this microRNAcluster in neuroblastoma biology. (Clin Cancer Res 2009;15(17):55608)