Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy

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.

Keywords: MEN1 gene; loss of heterozygosity (LOH); miR-24; microRNA (miRNAs); multiple endocrine neoplasia type 1 (MEN1).

Figure 1

Schematic representation of the autoregulatory network between miR-24-1, MEN1 mRNA, and menin. (A) menin binds the upstream region of the miR-24-1-encoding gene cluster on chromosome 9, promoting the transcription of pri-miR-24-1; (B) menin directly interacts with the primary transcript of miR-24-1, pri-miR-24-1, facilitating the DROSHA-mediated processing to pre-miR-24-1, in a positive feedforward loop in which menin promotes the maturation of the repressor of its own expression, miR-24-1. Mature miR-24-1, together with the RISC complex, binds the 3′ UTR of MEN1 mRNA blocking translation of menin.