Nuclear factor-{kappa}B contributes to anaplastic thyroid carcinomas through up-regulation of miR-146a.
BACKGROUND
Micro-RNAs (miRNAs) have been recently involved in the modulation of several biological activities including cancer. Many human tumors show deregulated expression of miRNAs targeting oncogenes and/or tumor suppressors, thus identifying miRNAs as new molecular targets for cancer therapy.


OBJECTIVE
Nuclear factor (NF)-kappaB 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-kappaB 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-kappaB. 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-kappaB contributes to anaplastic thyroid cancer up-regulating the expression of miR-146a.
Pacifico
Francesco
F
Dipartimento di Biologia e Patologia Cellulare e Molecolare, "Federico II" University of Naples, Via S. Pansini 5, 80131 Naples, Italy.
Crescenzi
Elvira
E
Mellone
Stefano
S
Iannetti
Alessio
A
Porrino
Nunzio
N
Liguoro
Domenico
D
Moscato
Fortunato
F
Grieco
Michele
M
Formisano
Silvestro
S
Leonardi
Antonio
A
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B