Neuroblastoma is a pediatric solid
tumor that originates from embryonic neural crest cells. The MYCN gene locus is frequently amplified in unfavorable
neuroblastomas, and the gene product promotes the progression of
neuroblastomas. However, the molecular mechanisms by which MYCN amplification contributes to stem cell-like states of
neuroblastoma remain elusive. In this study, we show that MYCN and its cis-antisense gene, NCYM, form a positive feedback loop with OCT4, a core regulatory gene maintaining a multipotent state of neural stem cells. We previously reported that NCYM is co-amplified with the MYCN gene in primary human
neuroblastomas and that the gene product promotes aggressiveness of
neuroblastoma by stabilization of MYCN. In 36 MYCN-amplified primary human
neuroblastomas, OCT4
mRNA expression was associated with unfavorable prognosis and was correlated with that of NCYM. The OCT4
protein induced both NCYM and MYCN in human
neuroblastoma cells, whereas NCYM stabilized MYCN to induce OCT4 and stem cell-related genes, including NANOG, SOX2, and LIN28. In sharp contrast to MYCN, enforced expression of c-MYC did not enhance OCT4 expression in human
neuroblastoma cells.
All-trans retinoic acid treatment reduced MYCN, NCYM, and OCT4 expression, accompanied by the decreased amount of OCT4 recruited onto the intron 1 region of MYCN. Knockdown of NCYM or OCT4 inhibited formation of spheres of
neuroblastoma cells and promoted asymmetric cell division in MYCN-amplified human
neuroblastoma cells. These results suggest that the functional interplay between MYCN, NCYM, and OCT4 contributes to aggressiveness of MYCN-amplified human
neuroblastomas.