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

Abstract

Neuroblastoma is the most common malignant disease of infancy, and amplification of the <i>MYCN</i> 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 <i>in vitro</i> and <i>in vivo</i>. kynurenine treatment also upregulated the expression of <i>KISS1</i>, a tumor metastasis suppressor, and attenuated metastasis in the xenograft model. Finally, analysis of <i>KISS1</i> levels in neuroblastoma patient tumors using the R2: Genomics Analysis and Visualization Platform revealed that <i>KISS1</i> expression positively correlated with <i>AHR</i>, and high <i>KISS1</i> 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.