Future studies should investigate the molecular and cellular mechanisms of tissue selectivity in MEN 1-associated tumorigenesis, in an effort to develop an RNA-based treatment that could prevent or delay the onset of MEN 1-associated tumors.
Germline mutations in MEN1 (encoding menin) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas, which highlights the importance of the chromosome 11q13 locus in pituitary tumorigenesis.
Here we studied the global microRNAs (miRNAs) expression profile in MEN1 parathyroid adenomas to understand the role of these regulatory factors in MEN1 parathyroid tumorigenesis. miRNA arrays containing 1890 human miRNAs were used to profile seven different MEN1 parathyroid adenomas (four presenting somatic loss of heterozygosity (LOH) at 11q13 and three still retaining one wild type copy of the <i>MEN1</i> gene).
Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis.
However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms.
In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis.
It has been shown that the multiple endocrine neoplasia tumor suppressor gene (MEN1) is mutated in parathyroid adenomas, and overexpression of the cyclin D1 oncogene [PRAD1 (parathyroid adenoma 1)] seems to contribute to parathyroid tumorigenesis.
Loss of heterozygosity (LOH) in the MEN1 region on chromosome 11q13 has been found in 30% of sporadic parathyroid tumors, making the recently cloned MEN1 gene a prime candidate for involvement in parathyroid tumorigenesis.
Mutations were present in both benign and malignant pancreatic endocrine tumors, suggesting that a MENIN gene mutation is a frequent and early event in the tumorigenesis.
Our data define mouse and rat MEN1 as widely expressed and highly conserved homologs of the human MEN1 tumor suppressor gene whose role in biology and endocrine tumorigenesis is due for experimental study.
Our findings reveal that menin plays an important epigenetic role in promoting liver tumorigenesis, and support the notion that H3K4me3, which is regulated by the menin-mixed-lineage leukemia complex, is a potential therapeutic target in hepatocellular carcinoma.
Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.
Parathyroid adenomas are usually benign uniglandular tumors, and inactivation of several tumor suppressor genes, notably the MEN 1 gene, or activation of oncogenes have been implicated in the tumorigenesis.
Somatic MEN1 gene mutations and deletions play a critical role in the tumorigenesis of sporadic gastrinomas and may also contribute to the development of a subgroup of insulinomas.