title: Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas.
abstract: 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.
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.|Cancer Genome Center, Chiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suenaga
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.
authors.forename: S M Rafiqul
authors.initials: SM
authors.lastname: Islam
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsumoto
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Cancer Genomics, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ohira
authors.affiliation: Cancer Genome Center, Chiba, Japan.
authors.forename: Sana
authors.initials: S
authors.lastname: Yokoi
authors.affiliation: Division of Biochemistry and Innovative Cancer Therapeutics and Children's Cancer Research Center, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis
chemical_list: C459801:MYCN protein, human; C000588908:MYCNOS protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; D015513:Oncogene Proteins; C494173:POU5F1 protein, human
keywords: MYCN; NCYM; OCT4; neuroblastoma; transcriptional regulation