title: A combined gene expression and functional study reveals the crosstalk between N-Myc and differentiation-inducing microRNAs in neuroblastoma cells.
abstract: MYCN amplification is the most common genetic alteration in neuroblastoma and plays a critical role in neuroblastoma tumorigenesis. MYCN regulates neuroblastoma cell differentiation, which is one of the mechanisms underlying its oncogenic function. We recently identified a group of differentiation-inducing microRNAs. Given the demonstrated inter-regulation between MYCN and microRNAs, we speculated that MYCN and the differentiation-inducing microRNAs might form an interaction network to control the differentiation of neuroblastoma cells. In this study, we found that eight of the thirteen differentiation-inducing microRNAs, miR-506-3p, miR-124-3p, miR-449a, miR-34a-5p, miR-449b-5p, miR-103a-3p, miR-2110 and miR-34b-5p, inhibit N-Myc expression by either directly targeting the MYCN 3'UTR or through indirect regulations. Further investigation showed that both MYCN-dependent and MYCN-independent pathways play roles in mediating the differentiation-inducing function of miR-506-3p and miR-449a, two microRNAs that dramatically down-regulate MYCN expression. On the other hand, we found that N-Myc inhibits the expression of multiple differentiation-inducing microRNAs, suggesting that these miRNAs play a role in mediating the function of MYCN. In examining the published dataset collected from clinical neuroblastoma specimens, we found that expressions of two miRNAs, miR-137 and miR-2110, were significantly anti-correlated with MYCN mRNA levels, suggesting their interactions with MYCN play a clinically-relevant role in maintaining the MYCN and miRNA expression levels in neuroblastoma. Our findings altogether suggest that MYCN and differentiation-inducing miRNAs form an interaction network that play an important role in neuroblastoma tumorigenesis through regulating cell differentiation.
authors.affiliation: Department of Chemistry and Biochemistry at Texas State University, San Marcos, Texas, USA.
authors.forename: Zhenze
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Greehey Children's Cancer Research Institute at UT Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Xiuye
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Chemistry and Biochemistry at Texas State University, San Marcos, Texas, USA.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Shelton
authors.affiliation: Division of Nutritional Sciences at Cornell University, Ithaca, New York, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Sung
authors.affiliation: University of Texas at Austin, Austin, Texas, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biology at Texas State University, San Marcos, Texas, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, Texas, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemistry & Biochemistry at St. Mary's University, San Antonio, Texas, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Losiewicz
authors.affiliation: Department of Epidemiology and Biostatistics, at UT Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Greehey Children's Cancer Research Institute at UT Health Science Center at San Antonio, San Antonio, Texas, USA.|Department of Pediatrics, at UT Health Science Center at San Antonio, San Antonio, Texas, USA.|Cellular and Structural Biology, at UT Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.affiliation: Graduate School of Biomedical Sciences at UT Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yu
authors.affiliation: Graduate School of Biomedical Sciences at UT Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Yuanhang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry at Texas State University, San Marcos, Texas, USA.
authors.forename: Liqin
authors.initials: L
authors.lastname: Du
mesh_terms: D020413:3' Untranslated Regions; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein
keywords: MYCN; differentiation; microRNA; neuroblastoma