Abstract
Neuroblastoma (NB) is the most common malignant disease of infancy. MYCN amplification is a prognostic factor for NB and is a sign of highly malignant disease and poor patient prognosis. In this study, we aimed to investigate novel MYCN-related genes and assess how they affect NB cell behavior. The different gene expression found in 10 MYCN amplification NB tumors and 10 tumors with normal MYCN copy number were analyzed using tissue oligonucleotide microarrays. Ingenuity Pathway Analysis was subsequently performed to identify the potential genes involved in MYCN regulation pathways. Aryl hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, was found to be inversely correlated with MYCN expression in NB tissues. This correlation was confirmed in a further 14 human NB samples. Moreover, AHR expression in NB tumors was found to correlate highly with histological grade of differentiation. In vitro studies revealed that AHR overexpression in NB cells induced spontaneous cell differentiation. In addition, it was found that ectopic expression of AHR suppressed MYCN promoter activity resulting in downregulation of MYCN expression. The suppression effect of AHR on the transcription of MYCN was compensated for by E2F1 overexpression, indicating that E2F1 is involved in the AHR-regulating MYCN pathway. Furthermore, AHR shRNA promotes the expression of E2F1 and MYCN in NB cells. These findings suggest that AHR is one of the upstream regulators of MYCN. Through the modulation of E2F1, AHR regulates MYCN gene expression, which may in turn affect NB differentiation.
Highlights
Neuroblastoma (NB) is a childhood tumor derived from a sympathoadrenal lineage of neural crest progenitor cells, and is the most common malignant disease of infancy
To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips (20173 genes)
In the patients with MYCN amplification, 6 patients died of disease at a follow-up of to 57 months, whereas in the 10 patients with normal MYCN copy number, only 1 patient died of disease at a follow-up of 10 to 200 months
Summary
Neuroblastoma (NB) is a childhood tumor derived from a sympathoadrenal lineage of neural crest progenitor cells, and is the most common malignant disease of infancy. NB cells exhibit similar characteristics to undifferentiated cells and often metastasize to distant organs [1]. 60% of patients diagnosed with NB display a stage IV disease and have very poor prognosis. The 5-year survival rate of patients with NB is no more than 30%, even with aggressive therapy [2]. 50% of patients with NB die from this tumor. Recent evidence suggests that NB cells exhibit the capacity to differentiate into mature cells and can be forced to differentiate upon treatment with retinoic acid, butyric acid, or cisplatin [4,5]. A number of molecules normally expressed during embryonic development, including HNK-1, neuropeptide
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