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

• Published in: The journal of clinical endocrinology and metabolism 2010-03, Vol.95 (3), p.1421-1430
• Main Authors: Pacifico, Francesco, Crescenzi, Elvira, Mellone, Stefano, Iannetti, Alessio, Porrino, Nunzio, Liguoro, Domenico, Moscato, Fortunato, Grieco, Michele, Formisano, Silvestro, Leonardi, Antonio
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Endocrinopathies; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Malignant tumors; Medical sciences; Thyroid. Thyroid axis (diseases); Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-1128

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)-κB 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-κB 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-κB. 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-κB contributes to anaplastic thyroid cancer up-regulating the expression of miR-146a. Constitutive activation of NF-κB in anaplastic thyroid cancer results in increased expression of miR-146a that, in turn, modulates the oncogenic properties of cancer cells.