MicroRNA deregulation in parathyroid tumours suggests an embryonic signature

Abstract

Primary hyperparathyroidism is a common endocrine disorder caused by abnormal tumour parathyroid cell proliferation. Parathyroid tumours show a great variability both in clinical features, such as the severity of PTH secretion, the rate and the pattern of cell proliferation, and genetic background. Studies aiming to develop new diagnostic markers and therapeutic approaches need a deeper definition of this variability. Dysregulation of microRNAs (miRNAs) has been shown to play an essential role in the development and progression of cancer. MiRNAs are small noncoding RNAs that inhibit the translation and stability of messenger RNAs (mRNAs). Here, data about the miRNA expression pattern in parathyroid normal and tumour glands were reviewed. Though available data in parathyroid tumours are very limited, the expression pattern of a subset of specific miRNAs clearly discriminated parathyroid carcinomas from normal parathyroid glands and, more clinically relevant, from parathyroid adenomas. Investigation showed that parathyroid tumours were characterized by an embryonic expression pattern of miRNAs such as miR-296, or the miRNA clusters C19MC and miR-371-3, typically in stem cells committed to differentiation or during human embryonic development, respectively. Further, miRNA profiles were correlated with tumour aggressive behaviour. Moreover, the interaction with the oncosuppressor menin suggests that miRNAs might modulate the function of the known oncosuppressors or oncogenes involved in parathyroid tumourigenesis and thus overseeing the tumour phenotype. In conclusion, miRNAs might provide new diagnostic markers and new therapeutic approaches by developing molecular miRNA-targeted therapies for the cure of parathyroid tumours, whose unique option is surgery.

Clinicopathological correlates of hyperparathyroidism

“…HIC1 (17p13) is a putative tumour suppressor gene, epigenetically deregulated in parathyroid tumours due to histone H3 lysine modification 212 213. Recently, aberrant expression of a panel of embryonic-related microRNAs has been described in a series of sporadic parathyroid tumours, suggesting a role for microRNA deregulation in parathyroid tumorigenesis 211 212…”

“…Additional molecular alterations identified in parathyroid carcinomas ( CCND1, CDKIs, MEN1, EZH2, RIZ1, RASSF1, GSK3B, WT1, APC, SFRP, HIC1 , CaSR, VDR and microRNA deregulation) are non-specific and can also occur in parathyroid adenomas 31 42 43 81 82 141 151 164 205 210 211 212 216 217 219. Of note, MEN1 mutations, one of the key drivers in parathyroid adenomas (20–40%), appear to be less frequent in carcinomas (10–15%) 31 42 81 141 225–229.…”

Sychronous parathyroid carcinoma and multifocial papillary thyroid carcinoma: a case report

“…Abnormal expression of microRNAs (miRNAs) also has an important role in the development and progression of PC. [5,6] Genetic syndromes are the only precisely defined risk factor. PC has been reported previously in cases with radiation exposure to the head and neck region, and in patients with secondary or tertiary hyperparathyroidism due to chronic renal insufficiency.…”

Molecular genetics and epigenetics of nonfamilial (sporadic) parathyroid tumours

“…In PAs and PCs, differential expression of several miRNAs has been observed in relation to normal parathyroid tissue; see recent review by Verdelli et al . . Expression of a subset of miRNAs might discriminate between PA and PC, but this needs to be validated in larger tumour cohorts.…”

“…WT1 seems to positively or negatively regulate Wnt/β‐catenin signalling depending on the context . Of the identified miRNAs that were upregulated in PAs and PCs , miR‐222 and miR‐372 seemed to regulate the expression of the Wnt signalling inhibitors DKK2 and DKK1, respectively . Lastly, expression of CCND1 (cyclin D1) is regulated positively by Wnt/β‐catenin signalling , probably contributing to the observed overexpression of cyclin D1 in PAs (without translocation), PCs and secondary hyperplastic glands.…”