The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

Morotti, Annamaria; Forno, Irene; Verdelli, Chiara; Guarnieri, Vito; Cetani, Filomena; Terrasi, Andrea; Silipigni, B.S. Rosamaria; Guerneri, B.S. Silvana; Andrè, Valentina; Scillitani, Alfredo; Vicentini, Leonardo; Ferrero, Stefano; Corbetta, Sabrina; Vaira, Valentina

doi:10.1002/jbmr.4154

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…Accordingly, regulation of the EMT pathway was one of the top enriched canonical pathways in metastatic compared to non-metastatic PCs. The contribution of lncRNAs to the development of malignant and benign parathyroid tumors has been investigated indifferent studies and some of them might be useful markers in differentiating PCs from PAs (Jiang et al 2019, Morotti et al 2020.…”

Section: :2mentioning

confidence: 99%

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Condello

Cetani

Denaro

et al. 2021

Endocrine-Related Cancer

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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.

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Section: :2mentioning

confidence: 99%

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Condello

Cetani

Denaro

et al. 2021

Endocrine-Related Cancer

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“…Fresh samples from 20 PAds surgically removed from patients affected with primary hyperparathyroidism were collected and used for gene expression analysis in total tissue RNAs; biochemical, hormonal, and clinical characteristics have been previously published [46]. Fresh samples from further 10 PAds were collected immediately after surgical removal, partly snap-frozen, and partly dissociated for cell cultures.…”

Section: Parathyroid Tissue Samplesmentioning

confidence: 99%

“…The GRch37/hg19 of the Human Genome Reference (March 2009) consortium was used as the reference genome. Data were partially previously published [46].…”

Section: Dna Extraction and Array Comparative Genomic Hybridization (Acgh) Analysismentioning

confidence: 99%

Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors

Tavanti

Verdelli

Morotti

et al. 2021

IJMS

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The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells 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 this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

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“…The GRch37/hg19 of the Human Genome Reference (March 2009) consortium was used as the reference genome. Data were partially published previously [25].…”

Section: Dna Extraction and Array Comparative Genomic Hybridization (Acgh) Analysismentioning

confidence: 99%

“…Transient silencing of the MEN1 gene in PAds-derived cells (n = 4; Figure 2B) increased SOX2 mRNA levels (Figure 2C), while it did not affect expression of both POU5F1/OCT4 and NANOG (data not shown). Moreover, we previously demonstrated that MEN1 silencing increased the expression of a set of long non-coding RNAs (lncRNAs) in PAds [25]. We focused the attention on the lncRNA HAR1B, whose expression has been found to be upregulated in PAds harboring the Chr.11-LOH and has been upregulated by MEN1-silencing [25].…”

Section: The Core Stem Cell Genes Sox2 Pou5f1/oct4 and Nanog Are Expressed In Parathyroid Tumorsmentioning

confidence: 99%

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

et al. 2021

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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 18% of parathyroid adenomas (PAds, n = 34) involving 5–30% of cells, while OCT4 and NANOG were expressed at the nuclear level in a more consistent subset of PAds involving 15–40% of cells. Most parathyroid carcinomas expressed the core stem genes. SOX2-expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures, silencing of the tumor suppressor gene MEN1 induced the expression of SOX2, likely through a MEN1/HAR1B/SOX2 axis, while calcium-sensing receptor activation increased SOX2 mRNA levels through YAP1 activation. In addition, inducing nuclear β-catenin accumulation in PAds-derived primary cultures by short-term incubation with lithium chloride (LiCl), SOX2 and POU5F1/OCT4 expression levels increased, while NANOG transcripts were reduced, and LiCl long-term incubation induced an opposite pattern of gene expression. In conclusion, detection of the core stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.

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The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

Cited by 13 publications

References 34 publications

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Gene expression profile in metastatic and non-metastatic parathyroid carcinoma

Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors

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

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