The embryonic transcription factor TBX1 plays a critical role in cell differentiation during organogenesis of the parathyroid glands. Here we demonstrated that TBX1 mRNA and protein were detected in human adult normal parathyroid tissues (n=3). Immunostaining showed that TBX1 protein was expressed in endothelial CD31+, alfa-SMA+ cells. By contrast, TBX1 mRNA and protein was expressed at higher levels in parathyroid typical adenomas (n=23), where TBX1 staining was positive in parathyroid PTH+ cells with a cytoplasmic and nuclear localization. Functional studies were performed in HEK293 cells as they expressed TBX1. The activation of the calcium sensing receptor (CaSR) by stimulating for 24-h HEK293 cells stably transfected with the human CaSR with 15 mM calcium as well as with 10100 nM R-568, the CaSR agonist cinacalcet, induced a significant reduction in TBX1 mRNA levels. Thus, CaSR downregulation in parathyroid tumours might be related with the TBX1 overexpression. Overexpression of TBX1 mRNA and protein were observed also in parafibromin-expressing parathyroid cancers (n=3). TBX1 mRNA and protein were downregulated in parafibromin negative parathyroid carcinomas (n=14), suggesting that Wnt/β-catenin activation might inhibit TBX1 expression. In HEK293 cells TBX1 mRNA were inhibited by β-catenin accumulation induced by 24-h treatment with 120 nM lithium chloride, while β-catenin degradation induced by 40-min pretreatment with 10100 nM calyculin A determined an increase in TBX1 mRNA levels. Further functional studies on the effect of silencing and transfection of TBX1 are ongoing. In conclusion, the present data demonstrated that: i) TBX1 is expressed in adult parathyroid tissues; ii) TBX1 impaired expression contributes to parathyroid tumorigenesis; iii) TBX1 is a new target of the CaSR and Wnt/β-catenin pathways. TBX1 provides a potential therapeutic target for parathyroid tumors.
30 Apr - 04 May 2011
European Society of Endocrinology