Neuroblastoma (NB) is a highly heterogenic childhood tumor, which arises from immature or precursor cells of the developing sympathetic nervous system. 20-30 % of all NB carry a MYCN-amplification, which is associated with an undifferentiated and more aggressive phenotype and a poor prognosis. MYCN, as the other members of the MYC network of transcription factors, is a crucial regulator of several important cellular processes, such as proliferation, apoptosis and differentiation.
Our group has previously identified microRNA miR-18a as key mediator of MYCN-inhibited estrogen receptor alpha (ERα) expression, which in turn results in reduced neuronal differentiation (Lovén et al., 2010). This study aims to investigate the effect of ectopic ERα expression on the morphology and functional response of NB cells with MYCN amplification. Here we show that overexpression of ERα was sufficient to induce a neuronal differentiation phenotype and to interfere with processes linked to tumorigenesis, including cell viability, migration and anchorage independent growth. Furthermore, overexpression and activation of ERα resulted in upregulation of the NGF (nerve growth factor) receptors TrKA and p75NTR, and NGF treatment induced a more robust neuronal differentiation, indicating a cross talk between NGF and estrogen signaling. Interestingly, both NGF receptors are linked to a better prognosis and correlate negatively with MYCN-amplification.
In conclusion, we have identified a novel mechanism for how amplification of MYCN contributes to an undifferentiated and thus more aggressive phenotype in neuroblastoma. We demonstrate that MYCN-induced miR-18a inhibits expression of ERα and thereby interferes with estrogen and NGF signaling-mediated neuronal differentiation and promotes processes linked to tumorigenesis. Our findings highlight that restoration and activation of ERα by, e.g. inhibition of miR18a, may be an interesting starting-point for the development of new therapeutic strategies against neuroblastoma.