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Dihydropyrimidinase-like proteins (DPYSLs) are a family of proteins developmentally regulated during maturation of the nervous system. Recently, members of the DPYSL family have been reported to be involved in cancer with low expression of DPYSL1 correlating with poor clinical outcomes in non-small cell lung cancer and functioning as a metastasis suppressor. Neuroblastoma (NB) is a tumor derived from precursor cells of the sympathetic nervous system and is the most common solid tumor in childhood. So far the biological functions of DPYSLs in NB remain elusive. Studying the potential roles of DPYSLs in NB may give us new insights into NB tumorigenesis. In the present study, using antibodies specific to different members of the DPYSL family, DPYSL1, DPYSL2 and DPYSL3, we investigated regulation of their expression and their subcellular distribution during retinoic acid (RA)-induced differentiation in NB cells. The correlation between DPYSLs and MYCN, a biomarker for poor prognosis of NB, was evaluated. We found that DPYSL3 levels increased during RA-induced cell differentiation. Downregulation of MYCN by small interfering RNA (siRNA) increased DPYSL3 levels, while upregulation of MYCN in non-MYCN NB cells decreased DPYSL3 levels. DPYSL1 and DPYSL2 expression didn't change during RA treatment or under different expression levels of MYCN. Moreover, a high level of DPYSL3 mRNA, but not that of DPYSL1 or DPYSL2 mRNA, was detected in tumors from advanced-stage NB that have a better survival. These data indicated that DPYSL3, not DPYSL1 or DPYSL2, is negatively regulated by MYCN and may be used as a potential biomarker for NB.