Multiple Endocrine Neoplasia Type 1: The Potential Role of microRNAs in the Management of the Syndrome

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited tumor syndrome, characterized by the development of multiple neuroendocrine tumors (NETs) in a single patient. Major manifestations include primary hyperparathyroidism, gastro-entero-pancreatic neuroendocrine tumors, and pituitary adenomas. In addition to these main NETs, various combinations of more than 20 endocrine and non-endocrine tumors have been described in MEN1 patients. Despite advances in diagnostic techniques and treatment options, which are generally similar to those of sporadic tumors, patients with MEN1 have a poor life expectancy, and the need for targeted therapies is strongly felt. MEN1 is caused by germline heterozygous inactivating mutations of the MEN1 gene, which encodes menin, a tumor suppressor protein. The lack of a direct genotype–phenotype correlation does not permit the determination of the exact clinical course of the syndrome. One of the possible causes of this lack of association could be ascribed to epigenetic factors, including microRNAs (miRNAs), single-stranded non-coding small RNAs that negatively regulate post-transcriptional gene expression. Some miRNAs, and their deregulation, have been associated with MEN1 tumorigenesis. Recently, an extracellular class of miRNAs has also been identified (c-miRNAs); variations in their levels showed association with various human diseases, including tumors. The aim of this review is to provide a general overview on the involvement of miRNAs in MEN1 tumor development, to be used as possible targets for novel molecular therapies. The potential role of c-miRNAs as future non-invasive diagnostic and prognostic biomarkers of MEN1 will be discussed as well.

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

“…In addition to miR-24, other miRNAs showed to be possibly involved in the MEN1 tumorigenesis or to be deregulated in the sporadic tumor counterparts of the neuroendocrine tissues commonly affected in MEN1 syndrome [ 25 ], and they should be further investigated by functional studies, as was done for miR-24, to assess their importance in MEN1-related tumor development and progression.…”

“…In the last two decades, tissue-specific altered activity and/or expression of miRNAs have been suggested as possible modulators of MEN1 tumorigenesis [ 22 , 23 , 24 , 25 ], acting synergically with the MEN1 mutation, indicating the miR-24 as a possible effector of tumor development.…”

MicroRNAs as Potential Biomarkers in Pituitary Adenomas

“…Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited syndrome characterized by the occurrence of pituitary, parathyroid, and pancreatic tumors in a single patient [ 91 ]. Regarding MEN1-associated PAs, Lines KE et al [ 92 ] studied the levels of three miRNAs, miR-16-1, miR-15a, and let-7a, demonstrated to be downregulated in different subtypes of non-MEN1 PAs [ 16 , 93 , 94 , 95 , 96 , 97 ], in pituitary neoplasms from heterozygous MEN1 mutant mice ( MEN1 +/− mice).…”

Are Non-Coding RNAs Useful Biomarkers in Parathyroid Tumorigenesis?

“…Different ncRNAs have several mechanisms of action. In particular, and of interest for this review, miRNAs regulate gene expression by interacting principally with 3′-UTR of mRNA target, by taking it to degradation or by preventing its translation [ 27 ]. LncRNAs can act in various ways, but generally they perform their function by acting as competitive endogenous RNAs (ceRNAs), by binding their miRNA targets and inhibiting the action of the latter [ 21 ].…”