Zhao, ZhenzeMa, XiuyeShelton, Spencer D.Sung, Derek C.Li, MonicaHernandez, DanielZhang, MaggieLosiewicz, Michael D.Chen, YidongPertsemlidis, AlexanderYu, XiaojieLiu, YuanhangDu, Liqin2020-04-152020-04-152016-10Zhao, Z., Ma, X., Shelton, S. D., Sung, D. C., Li, M., Hernandez, D., Zhang, M., Losiewicz, M. D., Chen, Y., Pertsemlidis, A., Yu, X., Liu, Y., & Du, L. (2016). A combined gene expression and functional study reveals the crosstalk between N-Myc and differentiation-inducing microRNAs in neuroblastoma cells. Oncotarget, 7(48), pp. 79358–79373.1949-2553https://hdl.handle.net/10877/9619MYCN 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.Text16 pages1 file (.pdf)endifferentiationmicroRNAneuroblastomaMYCNArticlehttps://doi.org/10.18632/oncotarget.12676