Micro RNA Profiling in Pediatric Cancers

目的：microRNAs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，以确定肿瘤特异性的microRNAs。我们还研究了microRNAs是否与它们的宿主基因协同调节。实验设计：我们使用微阵列对57个肿瘤移植瘤和代表10个不同的儿童实体瘤的细胞系进行了平行的microRNAs和mRNA表达谱分析。对于那些映射到宿主mRNA的microRNAs，我们计算了它们之间的相关性。结果：我们发现，通过无监督的分级聚类，大多数癌症类型基于它们的全局microRNA表达谱而聚在一起。14个microRNAs在横纹肌肉瘤和神经母细胞瘤之间有显著差异表达，其中8个在独立的患者肿瘤样本中得到验证。对microRNAs表达与宿主基因关系的研究表明，位于已知编码基因内的68个microRNAs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microRNAs中，OncomiR-1簇的7个microRNAs中有5个与其宿主基因MIRHG1显著相关(P&lt；0.01)。此外，MIRHG1的高表达与神经母细胞瘤的高分期和MYCN扩增显著相关，在两个独立的患者队列中，MIRHG1的表达水平可以独立于当前的神经母细胞瘤风险分层来预测神经母细胞瘤患者的预后。结论：儿童肿瘤表达肿瘤特异的microRNAs。OncomiR-1宿主基因MIRHG1的高表达与神经母细胞瘤患者的不良预后相关，表明该微RNA簇在神经母细胞瘤生物学中具有重要的致癌功能。(临床癌症研究2009年；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, we calculated 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)