Topic review

Multiple endocrine neoplasia type 1

Submitted by: Maria Luisa Brandi

Definition

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.

1. Introduction

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[1],2[2]]. The main affected organs are parathyroid glands, anterior pituitary, and the neuroendocrine cells of the gastro-entero-pancreatic tract. Morbidity and mortality of the disease are related to hormone over-secretion by endocrine functioning tumors, leading to the development of specific syndromes, and/or to the malignant progression of silent tumors, such as non-functioning neuroendocrine neoplasms of the pancreas and the thymus.

Medical therapies of MEN1 aim to control hormone over-secretion and tumor growth. No therapeutic intervention is definitively resolutive; given the genetic nature of the syndrome and the asynchronous development of tumors, MEN1 patients have a high prevalence of post-operative tumor recurrences, both in the parathyroids and the gastro-entero-pancreatic tract [[1]]. Therefore, there is a strong need for novel therapies acting at the molecular level and able to prevent tumors in the target neuroendocrine cells. The comprehension of molecular mechanisms underlying MEN1 tumorigenesis is fundamental to identify possible targets for the design of novel therapies [2[2]].

The MEN1 gene encodes menin, a nuclear protein which exerts a wide spectrum of key activities, such as control of cell cycle and apoptosis, regulation of gene transcription and chromatin structure, and DNA repair [[2]]. Loss of both wild type MEN1 copies, resulting in loss of menin functions, appears to be the trigger of tumor initiation in MEN1 target neuroendocrine cells. Epigenetic factors are the main suspected co-actors in driving tumor development and progression in MEN1 target neuroendocrine cells [[3]]. Alterations in the normal epigenetic regulation of gene transcription (histone modification and/or DNA methylation), following the loss of wild type menin activity, have been demonstrated to play an important role in the progression of MEN1 pancreatic neuroendocrine tumors [[4]].

Among epigenetic regulators of gene expression, microRNAs (miRNAs) have recently been shown to be involved in the development of various human malignancies, either acting directly as oncogenes (oncomiRs) or inhibiting the expression of tumor suppressor genes [[5]]. These molecules are non-coding small RNAs that normally negatively regulate gene expression by directly binding the 3′UTR of their target Through the activity of tissue- and cell-specific miRNAs, the organism regulates the expression of numerous genes, in a spatial and temporal way, granting the correct functionality of various and important biological processes [[6],[7]]. Alterations of expression and/or activity of one or more miRNAs can lead to disease development, including cancer.

In the last two decades, tissue-specific altered activity and/or expression of miRNAs have been suggested as possible modulators of MEN1 tumorigenesis [22[10],23[11],24[12],25[13]], acting synergically with the MEN1 mutation, indicating the miR-24 as a possible effector of tumor development.

Here, we review results from recent studies that demonstrate the existence of an autoregulatory network between miR-24, MEN1 mRNA, and menin, suggesting possible roles of this miRNA in MEN1 tumorigenesis, and we discuss the possibility to silence this molecule in MEN1 mutation carriers to prevent/reduce cancer development and/or progression.

2. The Autoregulatory Network between miR-24, MEN1, and Menin: A Possible Effector of MEN1 Tumorigenesis

miR-24 is encoded by two separated chromosomal locations: one gene cluster located on chromosome 9q22, which includes miR-23b, miR-27b, and miR-24-1; and a second gene cluster located on chromosome 19p13, which includes miR-23a, miR-27a, and miR-24-2 [26[14]]. The two miR-24 mature isoforms are identical in nucleotide sequencing, regardless of the different chromosomal origin.

The seed site of miR-24-1, which binds toMEN1mRNA 3′UTR, is highly conserved in humans, rats, mice, chickens, and dogs. The direct targeting ofMEN1mRNA was demonstrated in vitro for the first time in 2012 by Luzi et al. [27[15]] in the BON1 cells, a human cell line derived from a lymph node metastasis of a serotonin-secreting pancreatic neuroendocrine tumor [2[16]8], via luciferase report assays. Authors showed that the induced over-expression of miR-24-1, through the transfection of pri-miR-24, inhibited the expression of menin protein, while the silencing of the endogenous miR-24-1, through the transfection of a specific 2′-O-methyl-RNA miR-24-1 antisense, resulted in an increased expression of menin, suggesting the existence of a direct negative feedback loop between miR-24-1 and menin, which could have a role in MEN1 tumorigenesis.

Later, in 2016, the same research group [29[17]] demonstrated in BON1 cells that, in addition to the negative feedback loop between miR-24-1,MEN1 mRNA, and menin, there was also a feedforward loop in which menin protein directly binds to the pri-miR-24-1 (the primary mRNA precursor of miR-24-1), promoting the DROSHA-mediated processing to pre-miR-24-1 and, thus, the biogenesis of mature miR-24-1. Moreover, the specific siRNA-induced silencing of menin expression in BON1 cells resulted in a complete suppression of pri-miR-24-1 expression, indicating an essential and direct role of menin in miR-24-1 synthesis, that is exerted by acting both at the transcriptional and at the post-transcriptional modification levels of the miR-24-1 synthesis. Conversely, when an overexpression of menin is induced in BON1 cells, this leads to an increased expression of mature miR-24-1. Authors showed that menin specifically binds to pri-miR-24-1, but not to pri-miR-24-2, and that the silencing of menin expression had no effect on the pri-miR-24-2 expression and the processing to pre-miR-24-2.

The proposed autoregulatory network between miR-24-1, MEN1 mRNA, and menin is shown in Figure 1.

The regulatory network between miR-24,MEN1, and menin was demonstrated also in other species, than humans, in vitro and in vivo [30[18],31[19],32[20]]. Interestingly, Gao et al. [3[18]0] demonstrated, both by Target Scan algorithm-based prediction and by an in vitro study in neonatal rat cardiac myocytes, that miR-24 targets the CDNK1B mRNA, blocking translation of the encoded p27kip1protein, a negative regulator of cell cycle, resulting in a decreased G0/G1 arrest and in cell hypertrophy. Inactivating mutations of the CDNK1B tumor suppressor gene are responsible for the development of multiple endocrine neoplasia type 4 (MEN4), a clinical phenocopy of MEN1 [33[21]].

Luzi et al. first demonstrated a direct regulation of menin expression by miR-24-1 in parathyroid tissues from MEN1 patients [27[7]], suggesting an epigenetic oncogenic role of this miRNA The analysis of miR-24-1 expression profiles in parathyroid adenomas from MEN1 mutation carriers, in sporadic non-MEN1 tumor counterparts and in healthy parathyroid tissue, showed an inverse correlation in the expression profiles of miR-24-1 and menin, indicating a direct role of miR-24-1 in the post-transcriptional negative regulation of menin expression itself. This inverse correlation was present only when the wild type copy of the MEN1 gene was still retained in the tumoral tissue, while in MEN1 adenomas presenting LOH at the 11q13 locus, menin resulted to be unexpressed and miR-24-1 was expressed at a very low level. The chromatin immunoprecipitation (ChIP) analysis, with an anti-menin antibody, in parathyroid tissues from MEN1 patients, showed the occupancy of miR-24-1 promoter region by menin, only in parathyroid adenomas conserving one wild type copy of the MEN1 gene, but not in tumors presentingMEN1LOH, and it confirmed menin as a positive regulator of miR-24-1 expression, as previously demonstrated in BON1 cells [27[7]].

Results from this study suggested that, in MEN1-associated parathyroid tumors, after the first inherited germinal “hit”, the somatic onset and progression of neoplasia could be under the control of a negative feedback loop between menin protein and miR-24-1. Authors hypothesized that this regulatory network could mimic and substitute the second somatic “hit” of tumor suppressor inactivation in tissues in which MEN1 LOH has not yet occurred, probably representing an intermediate step before the irreversible genetic MEN1 LOH. 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, This mechanism could explain the proliferative changes in the neuroendocrine cells (hyperplasia) that precede neoplasia, and this could also be hypothesized for pancreatic, duodenal, and other MEN1-associated tumors.

Some years later, the same Research Group [34[8]] failed to find both miR-24-1 and miR-24-2 as differentially expressed between MEN1 parathyroid adenomas with somatic MEN1 LOH at 11q13 and MEN1 parathyroid adenomas still retaining one wild type copy of theMEN1gene when they performed a microarray expression profiling covering about 1890 human miRNAs and using ap-value < 0.05 and a log2fold change > 1.5 as parameters of statistical significance.

Grolmusz et al. [[9]] compared the expression of six potential MEN1-targeting miRNAs, including miR-24, in MEN1-associated parathyroid adenomas/hyperplasia with a germinal MEN1 mutation (16), in sporadic counterparts bearing a somaticMEN1 mutation (10) and in sporadic parathyroid lesions wild type for the MEN1 gene (40). Expression levels of miR-24 and miR-28 were found to be significantly higher in sporadic primary hyperparathyroidism (PHPT) tissues with respect to MEN1-associated adenomas/hyperplasia, both when all the sporadic samples were considered and when considering the two sporadic PHPT subgroups of samples positive for nuclear menin staining or of samples negative for nuclear menin staining separately. No significant expression differences were found between the MEN1 mutated vs. the MEN1 wild type nuclear menin-negative sporadic lesions. All these data seemed to identify the higher expression of miR-24 and miR-28 as two universal signatures of sporadic non-syndromic parathyroid hyperplasia/adenoma, independent of their somatic genetic profile.

In the duodenum and the pancreas, the MEN1 gene-associated heterozygote germline mutation causes hyperplasia of insulin- gastrin-, somatostatin-, and glucagon-secreting cells, resulting in a subsequent multifocal development of tumors. The great majority of tumors analyzed showed allelic deletion/inactivation of the second copy of the MEN1 gene, whereas the precursor lesions retained their MEN1 heterozygosity [35[9]]. Pancreatic endocrine tumors develop from beta islets, through a stage of islet hyperplasia in which the wild-type MEN1 allele is still retained. LOH at MEN1 locus has never been found in these enlarged islets and, therefore, these lesions are considered to be a precursor stage of the tumors.

In 2014, Vijayaraghavan et al. [36[10]] confirmed the presence of a feedback loop between miR-24 and menin, similar to that identified in parathyroids, in cell lines of endocrine pancreas (the MIN6 cells derived from a mouse insulinoma and the Blox5 cells, an immortalized cell line produced from a purified population of human pancreas beta cells by infection with retroviral vectors). Cell transfection with pre-miR-24 increased miR-24 levels and resulted in a reduction of MEN1 and menin expression, of 35% and 23% in MIN6 cells and 61% and 38% in Blox5 cells, respectively. Conversely, cell transfection with an anti-miR-24 antisense decreased endogenous miR-24 levels, in association with an increasedMEN1expression in MIN6 cells but not in Blox5 cells, and with no significant difference of menin expression in both MIN6 and Blox5 cells. The negative effect of menin depletion on miR-24 expression was also confirmed in vivo in a conditional knockout mouse model with a selective deletion of the MEN1 gene in pancreas beta cells, in which reductions of about 60% and 90% of miR-24 levels were found in heterozygote and homozygote knocked-out animals, respectively [36[10]].

In the same study, since in the pancreas menin is known to regulate gene expression in a transcription complex with mixed-lineage leukemia (MLL) factor, the Authors [36[10]] hypothesized the possibility that the miR-24-1- and miR-24-2-encoding genes could be targets of menin/MLL complex. The ChiP analysis in MIN6 and Blox5 cells showed that both menin and MLL proteins were present in the region upstream of miR-24, both on chromosomes 9 and 19, confirming the importance of the menin/MLL complex in miR-24 expression in pancreas islets.

Finally, since menin is known to negatively regulate cell proliferation by transcriptionally regulating expression of two main cell cycle inhibitors, p27kip1and p18ink4c, the Authors also investigated the impact of miR-24 expression on these two proteins. Inhibition of miR-24 expression by transfection with an anti-miR-24 antisense did not significantly affect p18 mRNA nor protein expression in MIN6 and Blox5 cells [36[10]]. In this way, the increased expression of miR-24, and the subsequent silencing of menin, lead to a significantly increased cell proliferation in Blox5 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.

Molecular effects of miR-24 in parathyroid glands and endocrine pancreas and possible roles in MEN1 tumorigenesis, reported in the currently available studies, are summarized in Table 1.

Menin has been found to exert its tumor suppression activity by blocking cell hyperplasia in tissues other than those commonly affected by MEN1 syndrome, such as prostate, breast, lung, liver, and stomach [37[11]].

Using the A549 cells (a continuous cell line derived from a human adenocarcinoma of the alveolar basal epithelium of the lungs) and the NCI-H446 cells (a cell line derived from a human small-cell lung tumor), Pan et al. [38[12]] also confirmed the interaction of miR-24 with the 3′UTR of MEN1 mRNA and the miR-24-mediated significant silencing of menin expression in lung cancer.

The induced overexpression of miR-24 in A549 cells inhibited menin expression and upregulated SMAD3 and cyclin D1, stimulating cell proliferation and, at the same time, increased expression of Bcl-2 and inhibited expression of Bax, resulting in the inhibition of cell apoptosis [38[12]]. Conversely, the induced silencing of endogenous miR-24 increased menin expression and downregulated SMAD3 and cyclin D1, inhibiting cell growth, and, at the same time, inhibited Bcl-2 expression and promoted Bax expression, allowing cell apoptosis [38[12]]. In addition, the induced overexpression of miR-24, in both A549 and NCI-H446 cell lines, upregulated SMAD3 and MMP2 and significantly enhanced cell migration and invasion, while downregulation of miR-24 decreased the expression of both SMAD3 and MMP2, preventing cell migration and invasion. Taken together, these data indicate miR-24 as an oncogenic effector in lung cancer cells, acting as promoter of both cell proliferation and metastatic spread.

In the same study, the analysis of surgical specimens from human lung cancer showed a higher expression of miR-24, and a mirrored lower expression of menin, in tumors with respect to the adjacent healthy tissues. miR-24 expression inversely correlated with tumor size and patient overall survival, while patients with a higher menin expression showed a longer survival rate [38[12]].

Bronchopulmonary carcinoids of the neuroendocrine cells of the bronchial epithelium arise in approximately 5–8% of MEN1 patients [39[13]]. Despite the different cytological origin with respect to lung cancers studied by Pan et al. [38[12]], an involvement of the miR-24-MEN1 mRNA-menin network in the tumorigenesis of these carcinoids in MEN1 syndrome cannot be excluded.

Although menin has been found to regulate cell proliferation in hepatocellular carcinoma [40[14]], the exact role of menin in liver carcinogenesis has not yet been widely studied, and the liver is not a site of primary tumor development in MEN1 syndrome, but only metastases from pancreas and duodenal MEN1-related neuroendocrine tumors. Ehrlich et al. [37[11]] studied the miR-24-MEN1 mRNA-menin network in six human cell lines of intrahepatic and extrahepatic cholangiocarcinoma (CCA), a biliary epithelial adenocarcinoma whose cells adopt a neuroendocrine-like phenotype during their proliferation. A further-induced silencing of menin in tumoral cells increased cell growth, while the induced menin overexpression reduced the cell proliferation rate together with a decreased cell migration and invasion.

All the six tumoral cell lines showed a basal overexpression of miR-24 with respect to the H69 control, as well as human CCA tumor samples compared with their matched healthy tissues. 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.

3. Targeting miR-24: A Potential Therapeutic Tool for MEN1 Tumorigenesis

The miR-24-driven post-transcriptional inhibition of menin synthesis, in parathyroid cells and pancreas beta islets, could represent an intermediate epigenetic step guiding the MEN1 tumorigenesis. menin has been demonstrated to have a role in the maintenance of genome stability and DNA repair, protecting cells from DNA damage [41[15],42[16]]. At the same time, the epigenetic silencing of wild type menin by miR-24 promotes cell proliferation and exposes cells to DNA damage, which could result in deletion at the 11q13 locus or mutation of the second copy of the MEN1 gene, favoring the somatic [6][17] LOH, which represents a common hallmark of MEN1 cancers in parathyroids and endocrine pancreas.

In light of this, it is conceivable that targeting and silencing the expression of miR-24 at this intermediate, still reversible, step, before the occurrence of the genetic, irreversible,MEN1LOH, could restore expression and activity of wild type menin and block neoplastic initiation and progression, representing a promising innovative tool for preventing tumor development and progression in MEN1 patients [43[18]].

This entry is adapted from 10.3390/ijms22147352

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  22. Ettore Luzi; Simone Ciuffi; Francesca Marini; Carmelo Mavilia; Gianna Galli; Maria Luisa Brandi; Analysis of differentially expressed microRNAs in MEN1 parathyroid adenomas. American journal of translational research 2017, 9, 1743-1753.
  23. Alberto Falchetti; Francesca Marini; Ettore Luzi; Francesca Giusti; Loredana Cavalli; Tiziana Cavalli; Maria Luisa Brandi; Multiple endocrine neoplasia type 1 (MEN1): Not only inherited endocrine tumors. Genetics in Medicine 2009, 11, 825-835, 10.1097/gim.0b013e3181be5c97.
  24. Jyothi Vijayaraghavan; Elaine C. Maggi; Judy S. Crabtree; miR-24 regulates menin in the endocrine pancreas. American Journal of Physiology-Endocrinology and Metabolism 2014, 307, E84-E92, 10.1152/ajpendo.00542.2013.
  25. Laurent Ehrlich; Chad Hall; Julie Venter; David Dostal; Francesca Bernuzzi; Pietro Invernizzi; Fanyin Meng; Jerome P. Trzeciakowski; Tianhao Zhou; Holly Standeford; et al.Gianfranco AlpiniTerry C. LairmoreShannon Glaser miR-24 Inhibition Increases Menin Expression and Decreases Cholangiocarcinoma Proliferation. The American Journal of Pathology 2017, 187, 570-580, 10.1016/j.ajpath.2016.10.021.
  26. Yunhu Pan; Hongmei Wang; Debin Ma; Zhiyu Ji; Limin Luo; Fangyu Cao; Fangfang Huang; Yangyang Liu; Yushu Dong; Yitan Chen; et al. miR‑24 may be a negative regulator of menin in lung cancer. Oncology Reports 2018, 39, 2342-2350, 10.3892/or.2018.6327.
  27. Carmen Montero; Pilar Sanjuán; María Del Mar Fernández; Iria Vidal; Héctor Verea; Fernando Cordido; Carcinoide bronquial y síndrome de neoplasias endocrinas múltiples TIPO 1. Aportación de un caso. Archivos de Bronconeumología 2010, 46, 559-561, 10.1016/j.arbres.2009.11.007.
  28. Ding Gang; Hua Hongwei; Liu Hedai; Zhang Ming; Huang Qian; Liao Zhijun; The tumor suppressor protein menin inhibits NF-κB-mediated transactivation through recruitment of Sirt1 in hepatocellular carcinoma. Molecular Biology Reports 2012, 40, 2461-2466, 10.1007/s11033-012-2326-0.
  29. A. Gallo; S. Agnese; I. Esposito; Mario Galgani; V.E. Avvedimento; Menin stimulates homology-directed DNA repair. FEBS Letters 2010, 584, 4531-4536, 10.1016/j.febslet.2010.10.032.
  30. Shenghao Jin; Hua Mao; Robert W Schnepp; Stephen M Sykes; Albert C Silva; Alan D D'andrea; Xianxin Hua; Menin associates with FANCD2, a protein involved in repair of DNA damage.. Cancer Research 2003, 63, 4204-4210.

Keywords

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