Poster Presentation Advances in Neuroblastoma Research Congress 2016

MYCN-regulated nuclear hormone receptors impact differentiation and survival in neuroblastoma patients (#236)

Diogo Ribeiro 1 , Ulrica Westermark 1 , Marcus Klarqvist 1 , Jakob Lovén 2 , Marie Henriksson 1
  1. Karolinska Institutet, Solna, Stockholm, Sweden
  2. Third Rock Ventures, Boston

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.