Mycn Regulates Nuclear Hormone Receptors And Impairs Differentiation And Survival In Neuroblastoma

Neuroblastoma is the most common extra-cranial solid tumor in children and arises from neural crest cells involved in the development of sympathetic nervous tissue. This childhood tumor is characterized by heterogeneity and amplification of the MYCN oncogene is highly associated with aggressive tumors and poor outcome. The aim of this study was to investigate the role of the MYCN-driven miR-17-92 cluster in neuroblastoma pathogenesis. In order to identify putative targets of miR-17-92 we performed in silico prediction analysis and found that miR-17-92 target sites are significantly enriched in the nuclear hormone receptor (NHR) super family, indicating a role for hormonal regulation in neuroblastoma tumorigenesis. Importantly, high expression of several of the NHRs correlated with increased event-free survival of neuroblastoma patients. By using non-MYCN amplified neuroblastoma cells with a tet-regulatable miR-17~92 we could verify a differentially expressed NHR profile in induced compared to uninduced cells. Interestingly, one of the most significantly dowregulated NHRs was the glucocorticoid receptor (GR). Moreover, luciferase reporter assays containing the wildtype or mutated 39UTR from the gene encoding GR demonstrate that it is a direct target of miR-17~92. Importantly, both MYCN and miR17~92 are able to downregulate GR. We further show that activation of GR signaling by dexamethasone induces differentiation markers and contributes to neural differentiation. Inhibition of MYCN activity and activation of GR signaling induced a significant reduction in tumor growth in a xenograft model of neuroblastoma. Taken together, our findings indicate an important role for miR-17-92 cluster in regulation of NHRs in neuroblastoma biology, with important implications for future therapeutic approaches in patients with MYCN-amplification. Citation Format: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Loven, Marie Arsenian Henriksson. MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B46.