Functional interplay between MYCN , NCYM , and OCT 4 promotes aggressiveness of human neuroblastomas
Author(s) -
Kaneko Yoshiki,
Suenaga Yusuke,
Islam S. M. Rafiqul,
Matsumoto Daisuke,
Nakamura Yohko,
Ohira Miki,
Yokoi Sana,
Nakagawara Akira
Publication year - 2015
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12677
Subject(s) - neuroblastoma , neural crest , biology , gene knockdown , cancer research , homeobox protein nanog , embryonic stem cell , microbiology and biotechnology , n myc , gene , neural stem cell , stem cell , cell culture , genetics , induced pluripotent stem cell , ganglioneuroma
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 OCT 4 , 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, OCT 4 mRNA expression was associated with unfavorable prognosis and was correlated with that of NCYM . The OCT 4 protein induced both NCYM and MYCN in human neuroblastoma cells, whereas NCYM stabilized MYCN to induce OCT 4 and stem cell‐related genes, including NANOG , SOX 2 , and LIN 28 . In sharp contrast to MYCN , enforced expression of c‐ MYC did not enhance OCT 4 expression in human neuroblastoma cells. All‐ trans retinoic acid treatment reduced MYCN , NCYM , and OCT 4 expression, accompanied by the decreased amount of OCT 4 recruited onto the intron 1 region of MYCN . Knockdown of NCYM or OCT 4 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 OCT 4 contributes to aggressiveness of MYCN ‐amplified human neuroblastomas.