ECE2013 Poster Presentations Endocrine tumours and neoplasia (66 abstracts)
The embryonic transcription factor TBX1 is expressed in adult parathyroid cells and might be involved in parathyroid tumorigenesis
Chiara Verdelli 1 , Valentina Varia 2 , Mirella Meregalli 3 , Annalisa Terranegra 4 , Vito Guarnieri 5 , Alfredo Scillitani 6 , Elena Passeri 7 , Leonardo Vocentini 8 , Stefano Ferrero 9 , Anna Spada 10 & Sabrina Corbetta 7
1Molecular Biology Laboratory, IRCCS Policlinico san Donato, San Donato Milanese (MI), Italy; 2Division of Pathology, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico-Milano, Milan, Italy; 3Laboratorio Cellule Staminali, Dipartimento di Fisiopatologia medico-chirurgica e dei Trapianti, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 4Department of Medicine, Surgery and Dentistry, Università di Milano, Milan, Italy; 5Medical Genetics, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 6Endocrine Unit, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 7Endocrine Unit, Department of Biomedical Sciences for Health, IRCCS Policlinico San Donato, Milan, Italy; 8Endocrine Surgery, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico-Milano, Milan, Italy; 9Department of Biomedical, Surgical and Dental Sciences, University of Milan Medical School and Division of Pathology, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy; 10Endocrine Unit, Department of Clinical Sciences and Community, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Cancer cells and embryonic stem cells share many key biological properties and have common genetic signature: transcription factors regulating self-renewal and differentiation have been found expressed in human cancer cells. We focused our attention on TBX1, the gene involved in 22q11.2 microdeletion/DiGeorge syndrome, which is involved in heart, thymic and parathyroid cells differentiation.
Real-time PCR, western blot and immunohistochemistry demonstrated that TBX1 mRNA and protein were expressed in normal parathyroid glands (n=3). Immunofluorescence (IF) showed a positive staining in parathyroid PTH+ cells with a cytoplasmic and nuclear localization. Typical parathyroid adenomas (n=23) expressed TBX1 at higher levels than normal glands. The regulation and the role of TBX1 gene in parathyroid adenomas were further investigated. Functional studies were performed in HEK293 cells, since they expressed TBX1 mRNA and protein. We tested the hypothesis that TBX1 expression might be regulated by signalling pathway involved in embryogenesis such as BMP/SMAD and Wnt/β-catenin. Treatment for 3–16 hours with 20 ng/ml BMP4 increased TBX1 mRNA levels. Interestingly, we found by IF that tumoral parathyroid cells expressed the BMP4 receptor BMPR1A. By contrast, TBX1 mRNA levels were inhibited by β-catenin accumulation induced by 8-hours of treatment with 10–20 nM lithium chloride. Furthermore, the activation of the calcium sensing receptor (CaSR) by stimulating for 24 hours HEK293 cells stably transfected with the human CaSR, with increasing calcium as well as R568 concentrations, the CaSR agonist cinacalcet, induced a reduction in TBX1 mRNA levels. Silencing of TBX1 gene in both HEK293 and tumoral parathyroid cells induced a significant reduction in TBX1 target genes such as WNT5a and BMP4-induced increase in inhibitor of differentiation-1 (Id1) mRNA expression levels. In conclusion, an embryonic signature has been identified in adult parathyroid cells and it is suggested to be involved in parathyroid tumorigenesis. New potential therapeutic targets for parathyroid tumours have been discovered.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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