Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative ‘tumour suppressor’ miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/− mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/− mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.
Highlights
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours (Pieterman et al 2009, Goudet et al 2010, Thakker et al 2012, Frost et al 2018)
Endocrinology in MEN1 NETs miR-16-1 (Fig. 1A, B and C). This revealed a significant increase in CCND1 mRNA levels in Men1+/− pituitary tumours (n = 5), when compared to normal pituitaries (n = 5) from WT mice (2.6-fold, P < 0.0005, Fig. 2A). These findings were confirmed by Western blot (Fig. 2B) and densitometry analyses (Fig. 2C), which revealed that expression of the cyclin D1 protein was significantly higher in the pituitary tumours than in those of the normal pituitaries
Analysis of the expression of a putative let-7a mRNA target, KRAS revealed significantly increased expression of KRAS, in the pituitary tumours of Men1+/− mice, when compared to normal pituitaries of Men1+/+ mice, a significant inverse correlation was not observed between the expression of KRAS and let-7a (Supplementary Fig. 3B)
Summary
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours (Pieterman et al 2009, Goudet et al 2010, Thakker et al 2012, Frost et al 2018). Loss of menin expression is observed in the majority of MEN1-associated tumours, in keeping with Knudson’s two-hit model of inherited tumourigenesis (Chandrasekharappa et al 1997, Concolino et al 2016, Lemos & Thakker 2008, Lemmens et al 1997). One mechanism that is likely to be implicated involves miRNAs, which have been reported to have roles in the development of a large number of other tumour types (Filipowicz et al 2008, Stefani & Slack 2008). The importance of miRNAs has been illustrated by their ability to influence a wide spectrum of cellular processes including proliferation, apoptosis and differentiation, in a tissue-specific manner and many miRNAs have been implicated in tumour development through the ability to influence the expression of a diverse set of target genes, including tumour suppressors and oncogenes (Peng & Croce 2016)
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