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Endocrine Abstracts (2015) 37 OC8.3 | DOI: 10.1530/endoabs.37.OC8.3

ECE2015 Oral Communications Endocrine tumours (5 abstracts)

miR-372 is aberrantly expressed in most parathyroid tumours and might contribute to parathyroid tumourigenesis by inhibiting CDKN1A/p21 and LATS2

Chiara Verdelli 1 , Irene Forno 2 , Valentina Vaira 2, , Vito Guarnieri 4 , Alfredo Scillitani 5 , Filomena Cetani 6 , Leonardo Vicentini 7 , Gianni Balza 8 , Edoardo Beretta 9 & Sabrina Corbetta 10


1Laboratory of Molecular Biology, IRCCS Policlinico San Donato, San Donato Milanese, MI, Italy; 2Division of Pathology, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; 3Istituto Nazionale Genetica Molecolare (INGM) Romeo ed Enrica Invernizzi, Milan, Italy; 4Medical Genetics, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy; 5Endocrinology Unit, IRCCS Hospital Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy; 6Endocrine Unit 2, Department of Clinical and Experimental Medicine, University Hospital of Pisa, University of Pisa, Pisa, Italy; 7Endocrine Surgery, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; 8General Medicine Unit, AO Alessandro Manzoni, Lecco, Italy; 9Endocrine Surgery, IRCCS Ospedale San Raffaele, Milan, Italy; 10Endocrinology and Diabetology Unit, Department of Biomedical Sciences fro Health, University of Milan, IRCCS Policlinico San Donato, San Donato Milanese, MI, Italy.


We previously described aberrant expression of microRNAs belonging to the chromosome 19 cluster (C19MC) and the close miR-371-373 cluster in two-thirds of parathyroid carcinomas (PCas). Therefore, we investigated the involvement of the miR-371-373 cluster in parathyroid tumours, where miR-372 was the most consistently upregulated. miR-372 is known to be highly expressed in human embryonic stem cells and definitely downregulated upon differentiation. Moreover, miR-372 promotes human somatic cell reprogramming. miR-372 was expressed at high levels (more than fourfold) in 48 out of 79 parathyroid tumours compared with the expression levels in normal parathyroid glands (n=5). miR-372 was expressed in more than 75% of both atypical parathyroid adenomas (PAds; n=18; 5.9±0.8-fold, P=0.003) and PCas (n=15; 5.1±1.1-fold, P=0.01) at levels significantly higher than those in typical PAds (n=46; 2.1±0.7-fold). miR-372 overexpression in HEK293 and MCF7 cells significantly downregulated mRNA and protein levels of the cyclin inhibitor kinase CDKN1A/p21 and of the large tumour suppressor kinase 2 (LATS2). Similarly, CDKN1A and LATS2 mRNA levels were significantly downregulated by the miR-372 overexpression in typical PAds-derived cells. miR-372 overexpression attenuated the Go/G1 checkpoint in the cell cycle, reducing the proportion of cells in the Go/G1 phase from 70 to 59%. Furthermore, miR-372 has been related with the ‘stemness’ Wnt/β-catenin signalling pathways. In 16 typical PAds we found that miR-372 levels were positively correlated with the nuclear β-catenin accumulation, investigated by western blot, and with the mRNA levels of the direct gene target of nuclear β-catenin transcriptional activity AXIN2. Nonetheless, in typical PAds-derived cells (n=6) miR-372 expression levels were not affected by lithium chloride-induced nuclear β-catenin accumulation. In conclusion, i) miR372 was aberrantly expressed in a subset of parathyroid tumours; ii) atypical PAds and PCas expressed miR-372 more frequently and at higher levels than typical PAds; iii) CDKN1A/p21 and LATS2 were targets of miR-372 inhibitory effects in PAds-derived cells; iv) miR-372 aberrant expression might impair Wnt/β-catenin pathway in parathyroid tumour cells.

Disclosure: This work was supported by the IRCCS Policlinico San Donato Research Found.

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