Nuclear Factor-κB Contributes to Anaplastic Thyroid Carcinomas through Up-Regulation of miR-146a

Abstract

Context:Micro-RNAs(miRNAs)havebeenrecentlyinvolvedinthemodulationofseveralbiological activitiesincludingcancer.ManyhumantumorsshowderegulatedexpressionofmiRNAstargeting oncogenesand/ortumorsuppressors,thusidentifyingmiRNAsasnewmoleculartargetsforcancer therapy. Objectives: Nuclear factor (NF)-B is strongly activated in human anaplastic thyroid carcinomas (ATCs). Because the regulation of miRNA expression is under control of RNA polymerase II-dependent transcription factors, we stably inactivated NF-B in the ATC-derived FRO cell line and analyzed its miRNA profile in comparison with the parental counterpart by using a miRNA chip microarray. Results: The analysis revealed that a number of miRNAs were differentially expressed in the two cell lines. Among others, the miR-146a showed a strong down-regulation that was confirmed by quantitative real time RT-PCR. The expression of miR-146a was almost undetectable in mouse embryonic fibroblasts isolated from the RelA knockout mice and was restored after reexpression of RelA, thus indicating that miR-146a transcription was controlled by NF-B. The inhibition of miR-146a expression in FRO cells decreased their oncogenic potential and increased the susceptibility to chemotherapeutic drug-induced apoptosis. No difference was found in the growth rate between untransfected and miR-146a-null FRO cells. Importantly, the miR-146a resulted in overexpression of human ATC specimens compared with the normal thyroid tissue. Conclusions: Our results show that NF-B contributes to anaplastic thyroid cancer up-regulating the expression of miR-146a. (J Clin Endocrinol Metab 95: 1421–1430, 2010)