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 3’UTR 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/or 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.