MicroRNAs 10a and 10b are potent inducers of neuroblastoma cell differentiation through targeting of nuclear receptor corepressor 2

Abstract

MicroRNAs function as negative regulators of post-transcriptional gene expression, playing major roles in cellular differentiation. Several neuroblastoma cell lines can be induced to undergo differentiation by all-trans-retinoic acid (ATRA) and are used for modelling signalling pathways involved in this process. To identify miRNAs contributing to differentiation, we profiled 364 loci following ATRA treatment of neuroblastoma cell lines and found miR-10a and miR-10b to be highly over-expressed in SK-N-BE, LAN5, and SHSY-5Y. Ectopic over-expression of these miRNAs led to a major reprogramming of the transcriptome and a differentiated phenotype that was similar to that induced by ATRA in each of these cell lines. One of the predicted down-regulated miR-10a/b targets was nuclear receptor co-repressor 2 (NCOR2), a co-repressor of gene transcription which is known to suppress neurite outgrowth. NCOR2 was experimentally validated as a direct target of miR-10a/b, and siRNA mediated inhibition of this mRNA alone resulted in neural cell differentiation. Moreover, induction of differentiation could be blocked by ectopic up-regulation of NCOR2 using an expression construct lacking the miR-10a/b 3’ UTR target site. We conclude that miR-10a/b play major roles in the process of neural cell differentiation through direct targeting of NCOR2, which in turn induces a cascade of primary and secondary transcriptional alterations, including the down-regulation of MYCN.

Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs

“…This miRNA is a potent inducer of neuroblastoma and muscle cell differentiation (Huang et al 2010, Foley et al 2011, Meseguer et al 2011. As leptin is involved in neuronal network organization in the hypothalamus, we suggest that blocking leptin action early in life promotes neuronal differentiation instead of proliferation leading to the impairment of energy homeostasis later in life as our findings suggest.…”

N-myc and Noncoding RNAs in Neuroblastoma

“…Overexpression of mir-101 and let-7e in MYCNamplified neuroblastoma cells diminished N-myc levels, and reduced proliferation and clonogenic growth. While mir-101 is generally sparsely expressed in neuroblastoma and has established tumor-suppressor functions in other cancers [(100) and references therein], let-7 family members are upregulated during neuroblastoma cell differentiation (47,56,78,(101)(102)(103), suggesting tumor suppressor functions for these miRNAs in neuroblastoma.…”

miRNAs as Essential Mediators of the Actions of Retinoic Acid in Neuroblastoma Cells

“…[2,[27][28][29][30]. To analyze the contribution of microRNA regulation to RA-induced differentiation of neuroblastoma cells, we have studied the changes in the pattern of expression of 667 different human miRNAs upon RA treatment of SH-SY5Y neuroblastoma cells.…”