The aberrantly expressed miR-372 partly impairs sensitivity to apoptosis in parathyroid tumor cells
Chiara Verdelli1, Irene Forno2,3, Annamaria Morotti2,3
1Laboratory of Experimental EndocrinologyIRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
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 (n = 15). Through in situ 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 CDKN1A/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 (PTH) mRNA levels, and it positively correlated in vivo with circulating PTH levels. Conversely, the parathyroid-specific genes TBX1 and GCM2 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.
Insights
Embryonic microRNA-372 (miR-372) is aberrantly expressed in parathyroid tumors, affecting apoptosis, parathyroid hormone (PTH) synthesis, and Wnt signaling pathways. This microRNA plays a role in parathyroid tumor development and progression.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Parathyroid tumors, including adenomas and carcinomas, frequently exhibit dysregulation of microRNAs, particularly those on chromosome 19.
- The embryonic microRNA miR-372 is implicated in various cancers, but its role in parathyroid tumorigenesis is not well understood.
Purpose of the Study:
- To investigate the expression and function of miR-372 in parathyroid tumors.
- To elucidate the molecular mechanisms by which miR-372 influences parathyroid tumor cell behavior, including apoptosis, hormone synthesis, and signaling pathways.
Main Methods:
- In situ hybridization to detect miR-372 expression in parathyroid tumor tissues.
- Transfection of parathyroid adenoma (PAd)-derived cells with miR-372 mimics.
- Analysis of target gene expression (CDKN1A/p21, LATS2, TBX1, GCM2, DKK1) at mRNA and protein levels.
- Assessment of cell viability and apoptosis induction (camptothecin treatment).
- Evaluation of parathormone (PTH) mRNA levels and Wnt pathway activity.
Main Results:
- miR-372 was aberrantly expressed in approximately half of parathyroid adenomas and most atypical adenomas/carcinomas.
- Ectopic miR-372 inhibited CDKN1A/p21 and LATS2 expression, blunted apoptosis, and increased PTH mRNA levels.
- miR-372 overexpression positively correlated with circulating PTH levels in vivo.
- miR-372 dampened the Wnt pathway by upregulating DKK1, without affecting TBX1 or GCM2 expression.
Conclusions:
- miR-372 is a novel oncogenic factor in a subset of parathyroid tumors.
- It contributes to tumor progression by reducing apoptosis sensitivity and increasing PTH synthesis.
- Dysregulation of miR-372 impacts Wnt signaling, offering potential therapeutic targets.
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