Abstract
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.
Original language | English (US) |
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Pages (from-to) | 76816-76826 |
Number of pages | 11 |
Journal | Oncotarget |
Volume | 7 |
Issue number | 47 |
DOIs | |
State | Published - 2016 |
Funding
We thank Jeremy Marks for technical support with our hypoxia experiments and the Computational Research Institute for their computing resources. LA1-55n and SK-N-BE2, were kind gifts from Dr. June Biedler. LAN-5 was a kind gift from Dr. Robert Seeger.This research was supported in part by the Neuroblastoma Children's Cancer Society (SLC), the Children's Neuroblastoma Cancer Foundation (SLC), Little Heroes Children's Cancer Research Fund (SLC), the Elise Anderson Neuroblastoma Research Fund (SLC), Bear Necessities Pediatric Cancer Foundation (MAA), the Cancer Research Foundation (MAA), and NIH Grant Numbers T32GM007019 (MAA), K12CA139160 (MAA), T32HL094282 (ARJ), and P50GM081892 (KPW). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Keywords
- Hypoxia
- Metabolism
- Neuroblastoma
- Pathway analysis
- RNA expression
ASJC Scopus subject areas
- Oncology