title: Aryl hydrocarbon receptor downregulates MYCN expression and promotes cell differentiation of neuroblastoma.
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.
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan ; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Liao
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsueh-Fen
authors.initials: HF
authors.lastname: Juan
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsuan-Cheng
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Bo-Jeng
authors.initials: BJ
authors.lastname: Wang
authors.affiliation: Degree Program of Translational Medicine, Academia Sinica-National Taiwan University, Taipei, Taiwan.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Lu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Shih
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Hsu
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008156:Luciferases; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D015513:Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D046888:Tissue Array Analysis
chemical_list: D017931:DNA Primers; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D009841:Oligonucleotides; D015513:Oncogene Proteins; D018336:Receptors, Aryl Hydrocarbon; D008156:Luciferases