A combined gene expression and functional study reveals the crosstalk between N-Myc and differentiation-inducing microRNAs in neuroblastoma cells
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Zhenze Zhao1, Xiuye Ma2, Spencer D. Shelton1, Derek C. Sung3, Monica Li4, Daniel Hernandez5, Maggie Zhang6, Michael D. Losiewicz7, Yidong Chen8, Alexander Pertsemlidis2,9,10, Xiaojie Yu11, Yuanhang Liu11, Liqin Du1
1Department of Chemistry and Biochemistry at Texas State University, San Marcos, Texas, USA
2Greehey Children’s Cancer Research Institute at UT Health Science Center at San Antonio, San Antonio, Texas, USA
3Division of Nutritional Sciences at Cornell University, Ithaca, New York, USA
4University of Texas at Austin, Austin, Texas, USA
5Department of Biology at Texas State University, San Marcos, Texas, USA
6Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, Texas, USA
7Department of Chemistry & Biochemistry at St. Mary’s University, San Antonio, Texas, USA
8Department of Epidemiology and Biostatistics, at UT Health Science Center at San Antonio, San Antonio, Texas, USA
9Department of Pediatrics, at UT Health Science Center at San Antonio, San Antonio, Texas, USA
10Cellular and Structural Biology, at UT Health Science Center at San Antonio, San Antonio, Texas, USA
11Graduate School of Biomedical Sciences at UT Health Science Center at San Antonio, San Antonio, Texas, USA
Liqin Du, email: firstname.lastname@example.org
Keywords: neuroblastoma, microRNA, differentiation, MYCN
Received: March 22, 2016 Accepted: September 13, 2016 Published: October 15, 2016
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.
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