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Activation of Aryl Hydrocarbon Receptor by Kynurenine Impairs Progression and Metastasis of Neuroblastoma

Authors :
Kuan-Hung Lin
Yu-Tzu Chang
Wei Min Chen
Shiu-Feng Huang
Mati Kargren
Yueh-Chien Lin
Chi-Hao Chang
Hsinyu Lee
I-Shing Yu
Ya-Yun Chan
Tzu-Hsuan Tseng
Yen Lin Liu
Tang-Long Shen
Yung-Feng Liao
Chien-Chin Chen
Yu-Ling Tai
Wen-Ming Hsu
Bo-Jeng Wang
Pei-Yi Wu
Hsueh Fen Juan
Source :
Cancer Research. 79:5550-5562
Publication Year :
2019
Publisher :
American Association for Cancer Research (AACR), 2019.

Abstract

Neuroblastoma is the most common malignant disease of infancy, and amplification of the MYCN oncogene is closely associated with poor prognosis. Recently, expression of MYCN was shown to be inversely correlated with aryl hydrocarbon receptor (AHR) expression in neuroblastoma, and overexpression of AHR downregulated MYCN expression, promoting cell differentiation. Therefore, we further investigated the potential of AHR to serve as a prognostic indicator or a therapeutic target in neuroblastoma. First, the clinical significance of AHR in neuroblastoma was examined. Positive AHR immunostaining strongly correlated with differentiated histology of neuroblastoma and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed neuroblastoma tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. kynurenine treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of KISS1 levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that KISS1 expression positively correlated with AHR, and high KISS1 expression predicted better survival for patients. In conclusion, our results indicate that AHR is a novel prognostic biomarker for neuroblastoma, and that overexpression or activation of AHR offers a new therapeutic possibility for patients with neuroblastoma. Significance: These findings show that AHR may function as a tumor suppressor in childhood neuroblastoma, potentially influencing the aetiologic and therapeutic targeting of the disease.

Details

ISSN :
15387445 and 00085472
Volume :
79
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi.dedup.....dad571dc0a0aaecaf55767702b4ebff0
Full Text :
https://doi.org/10.1158/0008-5472.can-18-3272