Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited multiple cancer syndrome of neuroendocrine tissues. Tumors are caused by an inherited germinal heterozygote inactivating mutation of the MEN1 tumor suppressor gene, followed by a somatic loss of heterozygosity (LOH) of the MEN1 gene in target neuroendocrine cells, mainly at parathyroids, pancreas islets, and anterior pituitary. Over 1500 different germline and somatic mutations of the MEN1 gene have been identified, but the syndrome is completely missing a direct genotype-phenotype correlation, thus supporting the hypothesis that exogenous and endogenous factors, other than MEN1 specific mutation, are involved in MEN1 tumorigenesis and definition of individual clinical phenotype. Epigenetic factors, such as microRNAs (miRNAs), are strongly suspected to have a role in MEN1 tumor initiation and development. Recently, a direct autoregulatory network between miR-24, MEN1 mRNA, and menin was demonstrated in parathyroids and endocrine pancreas, showing a miR-24-induced silencing of menin expression that could have a key role in initiation of tumors in MEN1-target neuroendocrine cells. Here, we review the current knowledge on the post-transcriptional regulation of MEN1 and menin expression by miR-24, and its possible direct role in MEN1 syndrome, describing the possibility and the potential approaches to target and silence this miRNA, to permit the correct expression of the wild type menin, and thereby prevent the development of cancers in the target tissues.
Highlights
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited cancer syndrome that causes the development of multiple endocrine and non-endocrine tumors in a single patient [1,2]
The pathway leading to MEN1 tumor development and progression could be explained by the proposed negative feedback loop between menin and miR-24-1 acting as a “homeostatic regulatory network” that needs to be “broken” to induce the somatic loss of heterozygosity (LOH) “hit” and, the progression to neoplasia
Results from this study clearly show that targeting miR-24 represents a promising therapeutic tool for reducing biliary tumor growth and suggest the possibility of using the same approach for other tumors, the tumorigenesis of which involves the oncomiR miR-24 and its inhibitory action on the MEN1 tumor suppressor gene
Summary
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited cancer syndrome that causes the development of multiple endocrine and non-endocrine tumors in a single patient [1,2]. The pathway leading to MEN1 tumor development and progression could be explained by the proposed negative feedback loop between menin and miR-24-1 acting as a “homeostatic regulatory network” that needs to be “broken” to induce the somatic LOH “hit” and, the progression to neoplasia This mechanism could explain the proliferative changes in the neuroendocrine cells (hyperplasia) that precede neoplasia, and this could be hypothesized for pancreatic, duodenal, and other. The fact that an increased expression of miR-24 reduced the expression of p27 and p18 mRNAs suggested this miRNA as negatively regulating the expression of these two cell cycle inhibitors in an indirect manner, via the suppression of menin translation In this way, the increased expression of miR-24, and the subsequent silencing of menin, lead to a significantly increased cell proliferation in Blox cells, but not in insulinoma-derived MIN6 cells, in which cell growth is already at such a high level as to not be further influenced by menin, p27, and p18 inhibition. The induced knock-down of miR-24 was associated with an increase of menin expression, a decreased expression of pro-angiogenic and pro-proliferative factors, and a reduction of cell proliferation and migration
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