Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy
Abstract
:1. Introduction
2. The Autoregulatory Network between miR-24, MEN1, and Menin: A Possible Effector of MEN1 Tumorigenesis
2.1. miR-24, MEN1 mRNA, and Menin in Parathyroid Glands
2.2. miR-24, MEN1 mRNA, and Menin in the Endocrine Pancreas
2.3. miR-24, MEN1 mRNA, and Menin in Non-MEN1 Tumors
3. Targeting miR-24: A Potential Therapeutic Tool for MEN1 Tumorigenesis
4. Future Research Needed in the Field of MEN1 Syndrome and miRNAs
5. Conclusions
- The absence of a genotype-phenotype correlation in MEN1 syndrome suggested a possible role of epigenetic factors in the development of the individual clinical phenotype in any single patient, even in presence of the same MEN1 mutation.
- miRNAs have shown increasing evidence of a direct role in human malignancies, both for sporadic and hereditary cancers. Several miRNAs resulted to be deregulated in the sporadic tumor counterparts of the neuroendocrine tissues commonly affected in MEN1 syndrome. A role of specific mi-RNA deregulation also in MEN1 tumorigenesis can be suspected.
- miR-24 has been demonstrated to negatively regulate menin expression in the parathyroids and the endocrine pancreas in MEN1 syndrome, and in other non-MEN1 sporadic tumors, suggesting it as initiator of menin loss-derived tumorigenesis.
- Targeting/silencing miR-24, during the hyperplastic phase of parathyroid and endocrine pancreas tumorigenesis and before the occurrence of the somatic MEN1 LOH, could by a promising tissue-specific RNA-based anti-cancer therapy, aimed to restore the correct expression of menin in pre-cancerous cells.
Author Contributions
Funding
Conflicts of Interest
References
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miR-24 Target | Effect | Possible Role in MEN1 Tumorigenesis | Reference |
---|---|---|---|
Parathyroid glands | |||
MEN1 | No effect on MEN1 mRNA expression. Loss of menin protein expression. | Uncontrolled cell proliferation | [27] |
Endocrine pancreas | |||
MEN1 | Reduction of both MEN1 mRNA and menin expression. | Uncontrolled cell proliferation | [36] |
CDKN1B | Reduction of expression of both CDKN1B mRNA and of p27kip1 protein in a mouse insulinoma cell line (MIN6). | Enhanced proliferation of beta-cells and hyperplasia of pancreas islets | [36] |
CDKN1B | Reduction of expression of CDKN1B mRNA in an immortalized human pancreas beta cell line (Blox5). No data on expression of p27kip1 protein. | Enhanced proliferation of beta-cells and hyperplasia of pancreas islets | [36] |
CDKN2C | No effect on expression of both CDKN2C mRNA and of p18Ink4c protein in a mouse insulinoma cell line (MIN6). | Non applicable | [36] |
CDKN2C | Reduction of expression of CDKN2C mRNA in an immortalized human pancreas beta cell line (Blox5). No data on expression of p18Ink4c protein. | Enhanced proliferation of beta-cells and hyperplasia of pancreas islets | [36] |
Therapeutic Tool | Description | Mechanism of Action on the Target oncomiR | Reference |
---|---|---|---|
Anti-miRNA oligonucleotides (AMOs) | Synthetic single-stranded RNA molecules complementary to the target miRNA | Competitive inhibition of the target mature miRNA by base pair | [44] |
Modified AMOs | AMOs with a chemical modification of the 2′-OH into 2′-O′methyl- or 2′-O′methoxyethyl- groups, to increase intracellular stability | Competitive inhibition of the target mature miRNA by base pair | [44] |
Antagomirs | AMOs with the 2′-O chemical modification and phosphorothioate bonds to increase intracellular stability and with a conjugated cholesterol tail at the 3′-end to favor cell membrane permeation | Competitive inhibition of the target mature miRNA by base pair | [45] |
Locked nucleic acids (LNA)-based AMOs | AMOs containing an additional methylene link between the 2′-O atom and the 4′-C atom, that locks ribose into a more thermodynamically stable conformation | High-affinity base pair with their target mature miRNA. Inhibition of miRNA activity | [46] |
Small molecules miRNA inhibitors | Small molecules (chemical compounds) that interfere with miRNA biogenesis and/or activity | Inhibition of a specific miRNA biogenesis and/or activity by chemical structure-based docking to miRNA precursor or to mature miRNA | [47] |
miRNA sponges | RNA transcripts presenting multiple tandem repeats of the binding site (seed sequence) of the miRNA to be targeted | They stably interact with the endogenous target miRNA, preventing its interaction with its target mRNAs | [48] |
miRNA masks | Single-stranded 2′-O′methyl-modified antisense oligonucleotides totally complementary to the miRNA binding sites in the 3′-UTR of the target mRNA | They “mask” the target mRNA from the endogenous miRNA, preventing the miRNA-driven suppression of protein translation | [49] |
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Marini, F.; Brandi, M.L. Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy. Int. J. Mol. Sci. 2021, 22, 7352. https://doi.org/10.3390/ijms22147352
Marini F, Brandi ML. Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy. International Journal of Molecular Sciences. 2021; 22(14):7352. https://doi.org/10.3390/ijms22147352
Chicago/Turabian StyleMarini, Francesca, and Maria Luisa Brandi. 2021. "Role of miR-24 in Multiple Endocrine Neoplasia Type 1: A Potential Target for Molecular Therapy" International Journal of Molecular Sciences 22, no. 14: 7352. https://doi.org/10.3390/ijms22147352