MicroRNAs 10a and 10b Are Potent Inducers of Neuroblastoma Cell Differentiation Through Targeting of Nuclear Receptor Co-repressor 2

Raymond L Stallings (1) , Niamh H Foley (1) , Isabella Bray (1) , Karen M Watters (1) , Kenneth Bryan (1) , Tytus Bernas (1) , Jochen H.M. Prehn (1)

1 Cancer Genetics

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.

Mots clés: neuroblastoma; MYCN; differentiation; retinoic acid; NCOR2

Raymond L Stallings, Niamh H Foley, Isabella Bray, Karen M Watters, Kenneth Bryan, et al.. MicroRNAs 10a and 10b Are Potent Inducers of Neuroblastoma Cell Differentiation Through Targeting of Nuclear Receptor Co-repressor 2. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2010.172⟩. ⟨hal-00606638⟩