1. Nuclear factor-{kappa}B contributes to anaplastic thyroid carcinomas through up-regulation of miR-146a.
- Author
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Pacifico F, Crescenzi E, Mellone S, Iannetti A, Porrino N, Liguoro D, Moscato F, Grieco M, Formisano S, and Leonardi A
- Subjects
- Analysis of Variance, Animals, Apoptosis drug effects, Apoptosis genetics, Blotting, Western, Carcinoma metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cells, Cultured, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunohistochemistry, Mice, MicroRNAs metabolism, Microarray Analysis, NF-kappa B metabolism, NF-kappa B pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Thyroid Neoplasms metabolism, Up-Regulation drug effects, Carcinoma genetics, MicroRNAs genetics, NF-kappa B genetics, Thyroid Neoplasms genetics, Up-Regulation genetics
- Abstract
Context: 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., Objectives: 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.
- Published
- 2010
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