Study of Aryl Hydrocarbon Receptor on the Regulation of MYCN Gene Expression in Neuroblastoma

• Main Authors: Pei-Yi Wu, 吳沛翊
• Other Authors: Hsinyu Lee
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/51706866100718233974

博士 === 國立臺灣大學 === 生命科學系 === 102 === 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, positive AHR expression by immunostaining of NB tumors was found to correlate well with histological grade of differentiation and predicted a favorable prognosis. 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-regulated 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. In order to further confirm the effect of AHR on the tumorigenesis of NB, the novel endogenous ligand of AHR, Kynurenine (Kyn), a tryptophan catabolite, was employed in the in vivo NB therapy experiments. It was found that Kyn could significantly prolong the survival of TH-MYCN transgenic mice and suppress metastasis of NB in the xenograft mice models. This result further suggests the important role of AHR in NB tumor progression.