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

Neuroblastoma (NB) 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 NB, 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 NB. First, the clinical significance of AHR in NB was examined. Positive AHR immunostaining strongly correlated with differentiated histology of NB and predicted better survival for patients. The mouse xenograft model showed that overexpression of AHR significantly suppressed NB tumor growth. In addition, activation of AHR by the endogenous ligand kynurenine (Kyn) inhibited cell proliferation and promoted cell differentiation in vitro and in vivo. Kyn treatment also upregulated the expression of KISS1, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Lastly, analysis of KISS1 levels in NB 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 NB, and that overexpression or activation of AHR offers a new therapeutic possibility for NB patients.