Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients.
Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients.
复制标题
DOI：
10.18632/oncotarget.12713
复制
发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Cohn SL
中科院分区：
文献类型：
--
作者：
Applebaum MA;Jha AR;Kao C;Hernandez KM;DeWane G;Salwen HR;Chlenski A;Dobratic M;Mariani CJ;Godley LA;Prabhakar N;White K;Stranger BE;Cohn SL
神经母细胞瘤以其广泛的临床表现而闻名，从自发消退到快速进展的疾病。众所周知，缺氧会使神经母细胞瘤表现出更具侵袭性的表型。我们分析了来自诊断性神经母细胞瘤肿瘤和缺氧性神经母细胞瘤细胞系的转录组数据，以鉴定其表达水平与患者预后不良相关并参与缺氧反应的基因。通过整合一组不同的转录组数据集，包括来自神经母细胞瘤患者和神经母细胞瘤衍生细胞系的数据集，我们确定了9个基因（SLCO 4A 1、ENO 1、HK 2、PGK 1、MTFP 1、HILPDA、VKORC 1、TPI 1和HIST 1H 1C），这些基因在缺氧中上调，并且其表达水平与三个独立的神经母细胞瘤队列中的不良患者结局相关。对5-羟甲基胞嘧啶和ENCODE数据的分析表明，这9个基因中至少有5个在缺氧中比常氧中具有5-羟甲基胞嘧啶的增加和更开放的染色质结构，并且是缺氧诱导因子（HIF）的推定靶点，因为它们在其调节区中含有HIF结合位点。其中四个基因是糖酵解途径的关键组成部分，另外三个基因直接参与细胞代谢。我们通过实验验证了我们的计算结果，证明在测试的四种神经母细胞瘤细胞系中，九种基因中的七种在缺氧反应中显著上调。这一紧凑和稳健验证的基因组与侵袭性神经母细胞瘤的缺氧反应相关，可能代表生物标志物和治疗开发的新靶点。
Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts. Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5-hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly validated group of genes, is associated with the hypoxia response in aggressive neuroblastoma and may represent a novel target for biomarker and therapeutic development.