A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation
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Zhenze Zhao1, Xiuye Ma1, Tzu-Hung Hsiao1, Gregory Lin1, Adam Kosti1, Xiaojie Yu2, Uthra Suresh1, Yidong Chen1,3, Gail E. Tomlinson1,4, Alexander Pertsemlidis1,4,5, Liqin Du1,5
1 Greehey Children’s Cancer Research Institute, UT Health Science Center at San Antonio, TX
2 Graduate School of Biomedical Sciences, UT Health Science Center at San Antonio, TX
3 Department of Epidemiology and Biostatistics, UT Health Science Center at San Antonio, TX
4 Department of Pediatrics, UT Health Science Center at San Antonio, TX
5 Department of Cellular and Structural Biology, UT Health Science Center at San Antonio, TX
Liqin Du, email:
Keywords: neuroblastoma, microRNA, high-content screen, differentiation, differentiation therapy
Received: December 14, 2013 Accepted: February 27, 2014 Published: February 28, 2014
Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy.
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