The aberrantly expressed miR-372 partly impairs sensitivity to apoptosis in parathyroid tumor cells

Abstract

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas ( = 15). Through hybridization, we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAd-derived cells, ectopic miR-372 inhibited the expression of its targets/p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAd-derived cultures. miR-372 overexpression in parathyroid tumor cells increased parathormone () mRNA levels, and it positively correlated with circulating PTH levels. Conversely, the parathyroid-specific genes and were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling.

Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors

“…The level of overexpression was similar to that observed in parathyroid cancers and significantly higher than in benign parathyroid adenomas. A significant reduction of mRNA levels of its target genes, namely CDKN1A (P21), large tumor suppressor kinase 2 (LATS-2) and CCDN1 (cyclin D1), as well as an inhibitory effect at protein level was also identified (Verdelli et al 2018).…”

“…miRNAs are small endogenous non-coding RNA molecules (18-25 nucleotides) which may repress protein expression. The only study addressing the role of miRNAs in atypical parathyroid adenoma was published in 2018, investigating the epigenetic signature of miRNAs in 19 atypical parathyroid adenomas compared with parathyroid carcinomas and adenomas (Verdelli et al 2018). An overexpression of miR-372 was found in 14 of 19 (74%) cases.…”

microRNA: The Impact on Cancer Stemness and Therapeutic Resistance

“…Moreover, miR-372 upregulates parathormone (PTH) gene expression as well. Interestingly, miR-372 upregulates DKK1 and downregulates CCND1 thus inhibiting the Wnt/β-catenin pathway, which may explain the limited proliferation ability of PAds [174].…”

“…In thyroid adenoma, C19MC and miR-371-3 clusters contribute to tumor development and CSC proliferation and enlargement [185]. In parathyroid tumors, miR-372 is upregulated to inhibit cell apoptosis, and increase PTH synthesis and cell proliferation [174]. C19MC-AAGUC miRNAs and miR-302/-372 are positively involved in tumorigenesis and cancer stemness through complex transcriptional regulatory mechanisms, which deserves continuing investigations and may provide a new prospect for CSC reprogramming and cancer therapy in the near future.…”

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer

“…Next, genomic DNA was extracted [53]. To evaluate the SCNAs of PTEN and the adjacent loci, a real-time PCR assay was employed (TaqMan, Thermo Fisher Scientific, Waltham, MA, USA), as described previously [54]. Three different regions within the PTEN genomic locus (Chr.10q23.31) were targeted using Hs05098450_cn (Chr10: 87,873,820 on GRCh38), Hs05153578_cn (Chr10: 87,949,592 on GRCh38), and Hs05182682_cn (Chr10: 88,024,586 on GRCh38) TaqMan assays, as detailed in Supplementary Figure S1.…”