ECE2016 Guided Posters Endocrine Tumours (10 abstracts)
Loss of cells expressing the T-box transcription factor TBX1 might be associated with a quiescent phenotype in parathyroid tumours
Chiara Verdelli 1 , Laura Avagliano 2 , Stefano Ferrero 3, , Vito Guarnieri 5 , Filomena Cetani 6 , Leonardo Vicentini 7 , Edoardo Beretta 8 , Alfredo Scillitani 9 , Gaetano Bulfamante 2 , Valentina Vaira 3, & Sabrina Corbetta 1
1Endocrinology Unit, Department of Biomedical Sciences for Health, University of Milan, IRCCS Policlinico San Donato, San Donato Milanese (MI), Italy; 2Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, Milan, Italy; 3Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy; 4Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Medical Genetics, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 6Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy; 7Endocrine Surgery, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; 8Endocrine Surgery, IRCCS Ospedale San Raffaele, Milan, Italy; 9Endocrine Unit, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 10Istituto Nazionale Genetica Molecolare (INGM) Romeo ed Enrica Invernizzi, Milan, Italy.
Embryonic transcription factors have been involved in tumourigenesis. The transcription factor TBX1 regulates the embryonic parathyroid cells fate. Indeed, it has never been investigated in human adult parathyroids. Here, expression, function and regulation of the TBX1 gene were analyzed in adult normal and tumour parathyroid tissues. Immunohistochemistry identified 30–70% (mean±S.E.M, 52.0±7.3%) of cells expressing TBX1 at nuclear levels in normal parathyroid glands (n=5). About a half of parathyroid tumours [12 parathyroid carcinomas and 13 adenomas (PAds)] had reduced TBX1+ cells (0–15%), showing deregulated TBX1 mRNA levels. Immunofluorescence on PAds-derived cells identified a subset of cells co-expressing TBX1 and PTH. Western blot analysis on fractioned proteins from PAds (n=11) showed that PAds expressed the 53 kDa isoform C of the TBX1 gene mainly at nuclear level. TBX1 function was investigated in HEK293 cells, which express the gene. Stable silencing of TBX1 gene in HEK293 cells reduced nuclear TBX1 protein to 30% of basal levels and increased the proportion of cells in the G0/G1 phase (from 38.2±6.7% to 50.2±9.1%, P=0.04), suggesting that loss of TBX1 induced cell cycle arrest. Consistent with the promotion of cell cycle arrest, TBX1 silencing increased CDKN2A/p16 and CDKN1A/p21 mRNA levels and decreased ID1 (inhibitor of DNA binding 1) levels both in HEK293 and PAds-derived cells, where any significant change in both GCM2 and PTH levels could be detected by TBX1-silencing. During embryonic development, TBX1 is regulated by the activation of the Wnt/β-catenin pathway. Short-term (8 h) 10–20 mM lithium chloride treatment induced β-catenin nuclear accumulation and inhibited TBX1 mRNA levels in five out of seven PAds cell preparations. Moreover, PAds samples with reduced TBX1 protein levels showed significantly higher AXIN2 mRNA levels, a marker of β-catenin transcriptional activity (median, IQR; 0.16, 0.05–0.65 vs 1.57, 0.38–2.93; P=0.03, n=11). In conclusion, the embryonic transcription factor TBX1 is expressed in a subpopulation of adult parathyroid cells, which is reduced in half of tumours. Reduction of TBX1 expression is associated with cell quiescence, a feature that might be in line with the extremely low cell proliferation rate described in parathyroid tumours.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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