Activation of aryl hydrocarbon receptor by kynurenine impairs progression and metastasis of neuroblastoma

Pei Yi Wu, I. Shing Yu, Yueh Chien Lin, Yu Tzu Chang, Chien Chin Chen, Kuan Hung Lin, Tzu Hsuan Tseng, Mati Kargren, Yu Ling Tai, Tang Long Shen, Yen Lin Liu, Bo Jeng Wang, Chi Hao Chang, Wei Min Chen, Hsueh Fen Juan, Shiu Feng Huang, Ya Yun Chan, Yung Feng Liao, Wen Ming Hsu, Hsinyu Lee

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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 down regulated 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.

Original languageEnglish
Pages (from-to)5550-5562
Number of pages13
JournalCancer Research
Volume79
Issue number21
DOIs
Publication statusPublished - Nov 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Wu, P. Y., Yu, I. S., Lin, Y. C., Chang, Y. T., Chen, C. C., Lin, K. H., Tseng, T. H., Kargren, M., Tai, Y. L., Shen, T. L., Liu, Y. L., Wang, B. J., Chang, C. H., Chen, W. M., Juan, H. F., Huang, S. F., Chan, Y. Y., Liao, Y. F., Hsu, W. M., & Lee, H. (2019). Activation of aryl hydrocarbon receptor by kynurenine impairs progression and metastasis of neuroblastoma. Cancer Research, 79(21), 5550-5562. https://doi.org/10.1158/0008-5472.CAN-18-3272