Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Abstract

Parathyroid carcinoma (PC) is one of the rarest and aggressive malignancies of the endocrine system. In some instances the histological diagnosis remains uncertain unless there is evidence of gross local invasion or secondary spread. The identification of molecular markers could improve the diagnostic accuracy of these lesions. The expression of 740 genes involved in the tumor progression processes was assessed in 8 parathyroid adenomas (PAs), 17 non-metastatic and 10 metastatic PCs using NanoString technology. Clustering analysis and Ingenuity Pathway Analysis (IPA) were interrogated to compare the gene expression profiles among the three analyzed groups and to evaluate the potential role of differentially expressed genes, respectively. The 103 differentially expressed genes between metastatic PCs and PAs are able to discriminate perfectly the two groups from a molecular point of view. The molecular signatures identified in non-metastatic PCs vs. PAs and in metastatic PCs vs. non-metastatic PCs comparisons, although with some exceptions, seem to be histotype-specific IPA reveals that hepatic fibrosis/hepatic stellate cell activation and GP6 signaling pathway are involved in malignant behavior of parathyroid tumors, whereas the activation of the HOTAIR regulatory pathway are involved in the metastatization process. Our investigation identified differentially expressed genes in non-metastatic PCs mainly encoding ECM proteins and in metastatic PCs driving endothelial-to-mesenchymal transition or encoding mediators of angiogenesis. The identified genes might be promising molecular markers potentially useful in the clinical practice for the early diagnosis and prognosis of PC.

The Core Stem Genes SOX2, POU5F1/OCT4, and NANOG Are Expressed in Human Parathyroid Tumors and Modulated by MEN1, YAP1, and β-catenin Pathways Activation

“…Cells expressing the core stem genes were detected in a subset of parathyroid adenomas and in most parathyroid carcinomas. In line with data reported by Condello et al [7], a metastatic parathyroid carcinoma expressed SOX2 in about 70% of cells. In PAds, SOX2-expressing cells co-expressed PTH, suggesting that re-expression of the early embryonic stem cell factor does not affect the endocrine properties of the parathyroid cells.…”

“…The IHC analysis for SOX2 failed to detect cells with specific nuclear staining in normal parathyroid glands (Figure 1A,D panel a and Supplementary Figure S1). This finding is in line with the Human Protein Atlas reports of IHC negative for SOX2 in human normal parathyroid glands (www.proteinatlas.org (accessed on 10 April 2021)) and with the recent report by Condello et al [7]. Similarly, most of PAds samples (n = 34) were negative for SOX2 immunostaining (Figure 1A).…”

“…Besides deregulation of the transcription factors TBX1 [6] and GCM2 [5], which are involved in parathyroid embryonic differentiation, and of microRNAs belonging to the early embryonic pluripotent C19MC microRNA cluster [9], parathyroid tumors harbor cells expressing the core stem genes SOX2, POU5F1/OCT4, and NANOG. Recently, SOX2 has been identified as significantly deregulated in parathyroid carcinomas [7]. In the present study, we focused our attention on the expression of SOX2 and investigation was extended to the associated core stem genes POU5F1/OCT4 and NANOG.…”

“…Parathyroid embryonic transcription factors are also expressed in parathyroid cells during adult life. Notably, their expression is aberrant in parathyroid tumors: HOX genes are deregulated in parathyroid benign tumors [2], activating variants of the glial cell missing 2 (GCM2) gene have been identified in familial and sporadic cases of PHPT [3][4][5], and the T-box transcription factor 1 (TBX1) gene is downregulated in parathyroid tumors [6,7]. Moreover, an embryonic epigenetic signature has been detected in parathyroid tumors [8]: the microRNA cluster C19MC, which is highly expressed in embryonic stem cells, is aberrantly expressed [9].…”

“…The expression of the core stem genes has been reported in a variety of human cancers [11] and in benign neoplasia [13][14][15]. Of note, by NanoString nCounter assay exploring the expression of 740 genes involved in the four major processes of tumor progression (angiogenesis, extracellular matrix, epithelial-mesenchymal transition, and metastasis), SOX2 gene expression has been recently detected in parathyroid cancers [7]. In addition, the core stem genes may be epigenetically modulated.…”