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MYCN-regulated microRNAs repress estrogen receptor-{alpha} (ESR1) expression and neuronal differentiation in human neuroblastoma.

In English

Författare

  • Jakob Lovén
  • Nikolay Zinin
  • Therese Wahlström
  • Inga Müller
  • Petter Brodin
  • Erik Fredlund
  • Ulf Ribacke
  • Andor Pivarcsi
  • Sven Påhlman
  • Marie Henriksson

Summary, in English

MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.

Avdelning/ar

Publiceringsår

2010

Språk

Engelska

Sidor

1553-1558

Publikation/Tidskrift/Serie

Proceedings of the National Academy of Sciences

Volym

107

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

National Academy of Sciences

Ämne

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1091-6490