The core stem genes SOX2, POU5F1/OCT4, and NANOG are expressed in human parathyroid tumors and modulated by MEN1, YAP1 and -catenin pathways activation.

Tumors of the parathyroid glands are the second most common endocrine neoplasia. Epigenetic studies revealed an embryonic signature involved in parathyroid tumorigenesis. Here we investigated the expression of the stem core genes SOX2, POU5F1/OCT4 and NANOG. Rare cells within normal parathyroid glands expressed POU5F1/OCT4 and NANOG, while SOX2 was undetectable. Nuclear SOX2 expression was detectable in 6 out of 34 (18%) parathyroid adenomas (PAds) involving 5-30% of cells, while OCT4 and NANOG were expressed at nuclear level in a more consistent subset of PAds involving 15-40% of cells. Most parathyroid carcinomas expressed the core stem genes. They were co-expressed in few PAds-derived cells, while SOX2-expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures (n=3), silencing of the tumor suppressor gene MEN1 induced the expression of SOX2, while calcium-sensing receptor activation inhibited SOX2 expression through YAP1 activation. Besides, inducing nuclear b-catenin accumulation in PAds-derived primary cultures (n=7) by short-term (8 hours) incubation with Lithium Chloride (LiCl, 10-20 mM), SOX2 and POU5F1/OCT4 expression levels increased, while NANOG transcripts were reduced; 72 hours with LiCl induced an opposite pattern of gene expression. In conclusion, detection of the cores stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.