Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas. Issue 7 (19th May 2015)

• Record Type: Journal Article
• Authors: Kaneko, Yoshiki; Suenaga, Yusuke; Islam, S. M. Rafiqul; Matsumoto, Daisuke; Nakamura, Yohko; Ohira, Miki; Yokoi, Sana; Nakagawara, Akira
• Is Part Of: Cancer science. Volume 106:Issue 7(2015:Jul.)
• Page Start: 840
• Page End: 847
• Publication Date: 2015-05-19
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12677
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" id="cas12677-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Neuroblastoma is a pediatric solid tumor that originates from embryonic neural crest cells. The <italic>MYCN</italic> gene locus is frequently amplified in unfavorable neuroblastomas, and the gene product promotes the progression of neuroblastomas. However, the molecular mechanisms by which <italic>MYCN</italic> amplification contributes to stem cell‐like states of neuroblastoma remain elusive. In this study, we show that <italic>MYCN</italic> and its <italic>cis</italic>‐antisense gene, <italic>NCYM</italic>, form a positive feedback loop with <italic>OCT4</italic>, a core regulatory gene maintaining a multipotent state of neural stem cells. We previously reported that <italic>NCYM</italic> is co‐amplified with the <italic>MYCN</italic> gene in primary human neuroblastomas and that the gene product promotes aggressiveness of neuroblastoma by stabilization of MYCN. In 36 <italic>MYCN</italic>‐amplified primary human neuroblastomas, <italic>OCT4 </italic>mRNA expression was associated with unfavorable prognosis and was correlated with that of <italic>NCYM</italic>. The OCT4 protein induced both <italic>NCYM</italic> and <italic>MYCN</italic> in human neuroblastoma cells, whereas NCYM stabilized MYCN to induce <italic>OCT4</italic> and stem cell‐related genes, including <italic>NANOG</italic>, <italic> SOX2</italic>, and <italic>LIN28</italic>. In sharp contrast to MYCN, enforced expression of c‐MYC did not enhance <italic>OCT4</italic> expression in human neuroblastoma cells. All‐<italic>trans</italic> retinoic acid treatment reduced MYCN, NCYM, and OCT4 expression, accompanied by the decreased amount of OCT4 recruited onto the intron 1 region of <italic>MYCN</italic>. Knockdown of NCYM or OCT4 inhibited formation of spheres of neuroblastoma cells and promoted asymmetric cell division in <italic>MYCN</italic>‐amplified human neuroblastoma cells. These results suggest that the functional interplay between MYCN, NCYM, and OCT4 contributes to aggressiveness of <italic>MYCN</italic>‐amplified human neuroblastomas.</p> </abstract>