ECE2021 Presented Eposters Presented ePosters 6: Calcium and Bone (8 abstracts)
Yes associated protein 1 (YAP1) expression and modulation by calcium sensing receptor activation in human parathyroid tumors
Giulia Stefania Tavanti 1 , Chiara Verdelli 1 , Paola Maroni 2 , Vito Guarnieri 3 , Alfredo Scillitani 4 , Rosamaria Silipigni 5 , Silvana Guerneri 5 , Riccardo Maggiore 6 , Gilberto Mari 6 , Leonardo Vicentini 7 , Paolo Dalino Ciaramella 8 , Annamaria Morotti 9 , Valentina Vaira 10 & Sabrina Corbetta 11
1Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 2Laboratory of experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 3Division of Medical Genetics, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 4Endocrinology Unit, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 5Medical Genetics Laboratory, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 6Endocrine Surgery, IRCCS Ospedale San Raffaele, Milan, Italy; 7Endocrine Surgery, IRCCS Istituto Auxologico, Milan, Italy; 8Endocrinology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 9Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 10Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy; 11Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
The Hippo pathway is involved in human tumorigenesis and regeneration. Here, we investigated the Hippo co-activator YAP1 and the kinase LATS1/2 in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands (n = 3), where YAP1 was detectable in the cytoplasm and in the nucleus, parathyroid adenomas (PAds; n = 10) had YAP1 accumulation mainly at the nuclear level, while in parathyroid carcinomas it was reduced at both nuclear and cytoplasmic levels (n = 6; 4 samples harboring CDC73 inactivating mutations and 2 samples harboring MEN1 inactivating samples). The kinase LATS1/2, which phosphorylates YAP1 promoting its cytoplasmic degradation and preventing its nuclear accumulation and transcriptional activity, was variably reduced in PAds. YAP1 and MEN1 map on chromosome 11, which is frequently interested by loss-of-heterozygosity in PAds; of note, YAP1 silencing appeared to reduce the expression levels of MEN1, while MEN1 silencing increased YAP1 expression in PAds-derived cell cultures and in HEK293A cells. Besides, YAP1 nuclear accumulation was induced by the calcium sensing receptor (CASR) agonist R568-mediated activation of the CASR in both PAds-derived cells and HEK293A cells transfected with CASR, and this effect was abolished upon the incubation with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and the effect was blunted by YAP1 silencing, suggesting that CASR-induced YAP1 nuclear accumulation is transcriptionally active in PAds-derived cells. Besides, YAP1 silencing did not affect PTH, CASR, TBX1, and VDR expression in PAds-derived cells, while YAP1 signaling may be partially involved in R568-stimulated GCM2 expression levels. Concluding, we provided evidence of the involvement of the Hippo pathway in human tumor parathyroid cells, suggesting a role as tumor suppressor for YAP1 and LATS1/2, and identifying the activation of a CASR-ROCK-YAP1 axis, where CASR activation induces YAP1 transcriptional action, and resistance to [Ca2+]o may reduce YAP1 nuclear accumulation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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