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Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas

Y Sugino1, A Misawa, J Inoue

  • 1Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.

Oncogene
|May 30, 2007
PubMed

Insights

Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is common in neuroblastoma (NB), particularly with MYCN amplification. Restoring PTGER2 inhibits NB cell growth, suggesting its role in neuroblastoma development.

Area of Science:

  • Molecular Biology
  • Cancer Genetics

Background:

  • Neuroblastoma (NB) is a pediatric cancer with complex genetic and epigenetic alterations.
  • Prostanoid receptors, including PTGDR and PTGER2, have been implicated in cancer development.

Purpose of the Study:

  • To investigate the role of epigenetic mechanisms, specifically DNA methylation and histone modifications, in the regulation of PTGER2 expression in neuroblastoma.
  • To determine the functional significance of PTGER2 in neuroblastoma cell growth and apoptosis.

Main Methods:

  • Bacterial artificial chromosome array-based methylated CpG island amplification.
  • Quantitative reverse transcription PCR for gene expression analysis.
  • Western blotting for histone modifications.
  • Cell culture, transfection, and treatment with agonists and cAMP analogs.

Main Results:

  • PTGER2 was frequently silenced in NB cell lines, especially those with MYCN amplification, via epigenetic mechanisms including DNA methylation and repressive histone modifications.
  • PTGER2 methylation and silencing were more prevalent in advanced-stage primary NBs.
  • Restoration of PTGER2 expression inhibited NB cell growth.
  • PTGER2 activation by butaprost increased intracellular cAMP, inhibited cell growth, and induced apoptosis in NB cells expressing PTGER2.
  • 8-Bromo-cAMP inhibited growth in NB cells lacking PTGER2, suggesting a disruption in the downstream signaling pathway.

Conclusions:

  • Epigenetic silencing of PTGER2 contributes to neuroblastoma progression.
  • PTGER2 plays a tumor-suppressive role in neuroblastoma through cAMP-dependent pathways.
  • Disruption of the PTGER2-cAMP pathway may lead to loss of growth inhibition and apoptosis in NB cells during tumorigenesis.

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