Biallelic inactivation of MEN1 encoding menin in pancreatic neuroendocrine tumors (PNETs) associated with the multiple endocrine neoplasia type 1 (MEN1) syndrome is well established, but how menin loss/inactivation initiates tumorigenesis is not well understood. We show that menin activates the long noncoding RNA maternally expressed gene 3 (Meg3) by histone-H3 lysine-4 trimethylation and CpG hypomethylation at the Meg3 promoter CRE site, to allow binding of the transcription factor cAMP response element-binding protein. We found that Meg3 has tumor-suppressor activity in PNET cells because the overexpression of Meg3 in MIN6 cells (insulin-secreting mouse PNET cell line) blocked cell proliferation and delayed cell cycle progression. Gene expression microarray analysis showed that Meg3 overexpression in MIN6 mouse insulinoma cells down-regulated the expression of the protooncogene c-Met (hepatocyte growth factor receptor), and these cells showed significantly reduced cell migration/invasion. Compared with normal islets, mouse or human MEN1-associated PNETs expressed less MEG3 and more c-MET. Therefore, a tumor-suppressor long noncoding RNA (MEG3) and suppressed protooncogene (c-MET) combination could elicit menin's tumor-suppressor activity. Interestingly, MEG3 and c-MET expression was also altered in human sporadic insulinomas (insulin secreting PNETs) with hypermethylation at the MEG3 promoter CRE-site coinciding with reduced MEG3 expression. These data provide insights into the β-cell proliferation mechanisms that could retain their functional status. Furthermore, in MIN6 mouse insulinoma cells, DNA-demethylating drugs blocked cell proliferation and activated Meg3 expression. Our data suggest that the epigenetic activation of lncRNA MEG3 and/or inactivation of c-MET could be therapeutic for treating PNETs and insulinomas.
The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent kinase inhibitor (CDKI) genes was raised by recognition of cyclin D1 as a parathyroid oncogene, identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1; that in rodents, mutation in Cdknlb caused parathyroid tumors; and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B, encoding p27kip1, in sporadic human parathyroid adenoma. We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and CDKN2D, encoding p21, p57, p14ARF/p16, p15, p18, and p19, respectively, contribute to the development of typical parathyroid adenomas. In a series of 85 sporadic parathyroid adenomas, direct DNA sequencing identified alterations in five adenomas (6 %): Two contained distinct heterozygous changes in CDKN1A, one germline and one of undetermined germline status; one had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); two had variants of CDKN2C, one somatic and one germline with LOH. Abnormalities of three of the mutant proteins were readily demonstrable in vitro. Thus, germline mutations/rare variants in CDKN1A, CDKN2B, and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas, and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells, providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasia.
5-Androstenediol (5-AED) stimulates hematopoiesis and enhances survival in animals exposed to ionizing radiation (IR), suggesting that this steroid may act on hematopoietic progenitor cells. We used ␥-irradiated primary human CD34 ϩ hematopoietic progenitor cells to show that 5-AED protects hematopoietic cells from IR damage, as shown by enhanced cell survival, clonogenicity, proliferation, and differentiation. Unlike in tumor cells, IR did not induce nuclear factor-B (NFB) activation in primary progenitors. However, IR stimulated IB  release from NFB/IB complexes and caused NFB1 (p50) degradation. 5-AED stabilized NFB1 in irradiated cells and induced NFB gene expression and NFB activation (DNA binding). 5-AED stimulated interleukin-6 and granulocyte colony-stimulating factor (G-CSF) secretion. The survival-enhancing effects of 5-AED on clonogenic cells were abrogated by small interfering RNA inhibition of NFB gene expression and by neutralization of G-CSF with antibody.
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