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Cancer Res. 2019 Nov 1;79(21):5550-5562. doi: 10.1158/0008-5472.CAN-18-3272. Epub 2019 Aug 20.

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

Author information

1
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
2
Laboratory Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan.
3
Department of Life Science, National Taiwan University, Taipei, Taiwan.
4
Department of Pathology, Chia-Yi Christian Hospital, Chiayi, Taiwan.
5
Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
6
Department of Plant Pathology and Microbiology & Center for Biotechnology, National Taiwan University, Taipei, Taiwan.
7
Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan.
8
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan.
9
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. hsinyu@ntu.edu.tw billwmhsu@gmail.com.
10
Department of Life Science, National Taiwan University, Taipei, Taiwan. hsinyu@ntu.edu.tw billwmhsu@gmail.com.
#
Contributed equally

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.

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