Nucleolar protein PES1 is a marker of neuroblastoma outcome and is associated with neuroblastoma differentiation.

Abstract

Neuroblastoma (NB) is a childhood malignant tumor that arises from precursor cells of the sympathetic nervous system. Spontaneous regression is a phenomenon unique to NBs and is caused by differentiation of tumor cells. PES1 is a multifunctional protein with roles in both neural development and ribosome biogenesis. Various kinds of models have revealed the significance of PES1 in neurodevelopment. However, the roles of PES1 in NB tumorigenesis and differentiation have remained unknown. Here we show that NB cases with MYCN amplification and clinically unfavorable stage (INSS stage 4) express higher levels of PES1. High PES1 expression was associated with worse overall and relapse-free survival. In NB cell lines, PES1 knockdown suppressed tumor cell growth and induced apoptosis. This growth inhibition was associated with the expression of NB differentiation markers. However, when the differentiation of NB cell lines was induced by the use of all-trans retinoic acid, there was a corresponding decrease in PES1 expression. Pes1 expression of tumorspheres originated from MYCN transgenic mice also diminished after the induction of differentiation with growth factors. We also reanalyzed the distribution of PES1 in the nucleolus. PES1 was localized in the dense fibrillar component, but not in the granular component of nucleoli. After treatment with the DNA-damaging agent camptothecin, this distribution was dramatically changed to diffuse nucleoplasmic. These data suggest that PES1 is a marker of NB outcome, that it regulates NB cell proliferation, and is associated with NB differentiation.

• Authors: Masato Nakaguro, Shinichi Kiyonari, Satoshi Kishida, Dongliang Cao, Yuko Murakami-Tonami, Hitoshi Ichikawa, Ichiro Takeuchi, Shigeo Nakamura, Kenji Kadomatsu
• Journal: Cancer science (Cancer Sci) Vol. 106 Issue 3 Pg. 237-43 (Mar 2015) ISSN: 1349-7006 [Electronic] England
• PMID: 25557119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Cell Cycle Proteins
• MYCN protein, mouse
• N-Myc Proto-Oncogene Protein
• Pes1 protein, mouse
• Proteins
• Proto-Oncogene Proteins
• RNA, Small Interfering
• RNA-Binding Proteins
• Tretinoin
• Camptothecin

Topics

• Animals
• Apoptosis (genetics)
• Camptothecin (pharmacology)
• Cell Cycle (genetics)
• Cell Cycle Proteins
• Cell Proliferation (genetics)
• Humans
• Mice
• Mice, Transgenic
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (genetics)
• Prognosis
• Proteins (genetics)
• Proto-Oncogene Proteins (genetics)
• RNA Interference
• RNA, Small Interfering
• RNA-Binding Proteins
• Tretinoin (pharmacology)
• Tumor Cells, Cultured