Stem cell genes are deregulated in parathyroid tumours

V. Vaira; C. Verdelli; I. Forno; F. Elli; V. Guarnieri; S. Ferrero; A. Scillitani; E. Costa; L. Vicentini; G. Steffano; F. Cetani; A. Spada; S. Bosari; S. Corbetta

In our previous investigation on microRNAs expression pattern in parathyroid carcinomas (Ca), we detected the over-expression of microRNAs belonging to C19MC, the largest human cluster on chromosome 19q13.41. In the present study, the analysis of the expression of selected C19MC and the closely distal MIR371-3 clusters microRNAs (MIR512-3p, MIR517C, MIR520H and MIR372) was extended to 11 Ca, 24 adenomas (Ad) and 6 normal glands. The four microRNAs was expressed in 11% of parathyroid neoplasia. Almost all Ca showed elevated MIR517C levels compared to normal glands, while MIR517C over-expression occurred only in two Ad. MIR372 was detected in 45.5% of Ca and in 37.5% of Ad. By copy number variation analysis, C19MC amplification was identified in most Ca extending distal to the MIR371-3 cluster in almost all amplified samples. Conversely, C19MC amplicon was detected in a small subset of Ad extending distal to MIR371-3 in one sample. C19MC promoter was hypomethylated in 38% of the samples with no difference in frequency between Ad and Ca. Few tumours did not show C19MC amplicon nor hypomethylation.

Since the C19MC as well as the MIR371-3 clusters have been linked with the signature characteristic for human embryonic stem cells, we investigated genes of the transcriptional regulatory network governing stem cells pluripotency and self-renewal. By immunohistochemistry, cells with a positive nuclear staining for NANOG were more abundant in Ca (50–70%) compared to normal glands (<10%) and to Ads (5–20%). In parathyroid tumours, NANOG expression was associated with the expression of OCT4 and the loss of the OCT4-inhibited gene DKK1, while SOX2 was undetectable evidencing an impairment of the core regulatory circuit. Moreover, zfp42/REX1 gene expression was lost in some tumours, as described in other human cancers. These data identified a genetic stem cell signature in parathyroid tumours that seems to correlate with more aggressive tumoral features.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Endocrine Abstracts

P806