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Institute of Endocrine Sciences, and
¹ Endocrine Surgery, Fondazione Ospedale Maggiore IRCCS, University of Milan, via F Sforza 32, 21122 Milan, Italy
² Pathology Unit, Department of Medicine, Surgery and Dentistry, Azienda Ospedaliera San Paolo, Milan, Italy
³ Laboratorio Sperimentale di Ricerche Endocrinologiche, Istituto Auxologico Italiano IRCCS, Milan, Italy

(Requests for offprints should be addressed to A Spada; Email: anna.spada{at}unimi.it)

Previous studies indicate that nuclear factor kappaB (NF-B) transcription factor is deregulated and overexpressed in several human neoplasias. The aim of this study was to test the hypothesis that the NF-B pathway may be involved in parathyroid tumorigenesis. For this purpose, we determined the level of NF-B activity, evaluated as phosphorylation of the transcription subunit p65, its modulation by specific and non-specific agents and its impact on cyclin D1 expression. Phosphorylated p65 levels present in parathyroid neoplasias (n = 13) were significantly lower than those found in normal tissues (n = 3; mean optical density (OD) 0.19 ± 0.1 vs 0.4 ± 0.1, P = 0.007), but there was no significant difference between adenomas and secondary and multiple endocrine neoplasia type 1 (MEN1)-related hyperplasia. Conversely, MEN2A (Cys634Arg)-related parathyroid samples showed extremely high levels of phosphorylated p65 that exhibited a nuclear localization at immunohistochemistry (n = 3). Phosphorylated p65 levels negatively correlated with menin expression (r² = 0.42, P = 0.05). Tumor necrosis factor- (TNF) caused a significant increase in phosphorylated p65 levels (183 ± 13.8% of basal) while calcium sensing receptor (CaR) agonists exerted a significant inhibition (19.2 ± 3.3% of basal). Although TNF was poorly effective in increasing cyclin D1 expression, NF-B blockade by the specific inhibitor BAY11-7082 reduced FCS-stimulated cyclin D1 by about 60%. Finally, the inhibitory effects of CaR and BAY11-7082 on cyclin D1 expression were not additive – by blocking NF-B CaR activation did not induce a further reduction in cyclin D1 levels. In conclusion, the study demonstrated that in parathyroid tumors: (1) p65 phosphorylation was dramatically increased by RET constitutive activation and was negatively correlated with menin expression, (2) p65 phosphorylation was increased and reduced by TNF and CaR agonists respectively, and (3) blockade of the NF-B pathway caused a significant decrease in cyclin D1 expression.

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