Original ResearchFull Report: Basic and Translational—Alimentary TractGastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells
Section snippets
Human Samples
De-identified surgical samples of human gastrinoma from 1996 to 2007 were obtained from the Department of Pathology at the University of Michigan, Center for Tumor Biology Barts Cancer Institute, Queen Mary University, London and the Royal Liverpool University Hospital, Liverpool, UK and are listed in Table 1. Sample access was approved by University of Michigan Institutional Review Board #HUM00115310.
Animals and Cell Culture
All animal experiments were approved by the University of Michigan's Committee on the Use and
Gastrin-expressing Cells Identified in Duodenal Lamina Propria
We previously showed that the OMS mice develop gastric carcinoids in the stomach corpus.20 Examination of the duodenums of these mice revealed numerous gastrin-positive cells in the lamina propria (LP-Gastrin+; Figure 1A and B). LP-Gastrin+ cells almost disappeared 4 months after withdrawal of omeprazole (OM), respectively (Figure 1C). H&E analysis revealed misshapen villi and dilated lamina propria in the OMS mice that returned to normal 4 months after withdrawing OM (Supplementary Figure 1A).
Discussion
Menin functions as a tumor suppressor in neuroendocrine tumors, including gastrinomas.36 Accordingly, we previously showed that modulating menin levels directly regulates gastrin gene expression through JUND in cell lines.17, 18 However, deleting Men1 from the intestinal epithelium does not induce gastrinomas, suggesting that modulating additional loci restricted to the spectrum of tissues developing neuroendocrine tumors contribute to the neoplastic transformation of gastrin-expressing
Acknowledgments
The authors thank Linda Samuelson for critically reviewing the manuscript, and support from R37 DK045729, Digestive Disease Center, UM Cancer Center Cores.
References (47)
- et al.
Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas
Gastroenterology
(2005) - et al.
Animal models of multiple endocrine neoplasia
Mol Cell Endocrinol
(2016) - et al.
Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system
Curr Opin Cell Biol
(2015) - et al.
Effect of bombesin-stimulated gastrin on gastric acid secretion in man
Life Sci
(1980) - et al.
Gastrin increases its own synthesis in gastrointestinal cancer cells via the CCK2 receptor
FEBS Lett
(2010) - et al.
Regulation of GPCR signaling in hypertension
Biochim Biophys Acta
(2010) - et al.
The role of cAMP and its downstream targets in neurite growth in the adult nervous system
Neurosci Lett
(2017) - et al.
Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione
Gastroenterology
(2007) - et al.
Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin
Lancet
(1989) - et al.
Secretin and vasoactive intestinal peptide receptors: members of a unique family of G protein-coupled receptors
Gastroenterology
(1998)
Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states
Hum Mol Genet
Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues
Mol Cell Biol
Localization of the multiple endocrine neoplasia type I (MEN1) gene based on tumor loss of heterozygosity analysis
Cancer Res
Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene
Hum Mutat
Four neuroendocrine tumor types and neuroendocrine carcinoma of the duodenum: analysis of 203 cases
Neuroendocrinology
Brunner's glands: a structural, histochemical and pathological profile
Prog Histochem Cytochem
Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions
Gut
Syndromic versus non-syndromic sporadic gastrin-producing neuroendocrine tumors of the duodenum: comparison of pathological features and biological behavior
Virchows Arch
Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas
Cancer Res
Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors
Cancer Res
DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors
Science
Homozygous loss of menin is well tolerated in liver, a tissue not affected in MEN1
Mamm Genome
A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors
Proc Natl Acad Sci U S A
Cited by (22)
GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming
2022, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Thus, gastric NET development in VillinΔMen1 mice likely requires non-glial cell autonomous signaling from the epithelium. Furthermore, human duodenal NETs are known to express glial cell markers, with some cells within the tumor exhibiting expression of both the neuroendocrine marker SYP and the glial-specific protein S100B.14,73 We recently used digital spatial profiling to characterize neuroglial features in a small subset of human duodenal NETs.73
Enteric glia in homeostasis and disease: From fundamental biology to human pathology
2021, iScienceCitation Excerpt :Patients with multiple endocrine neoplasia type 1 (MEN1) are prone to developing gastrin-secreting neuroendocrine tumors, gastrinomas, in the duodenum (Anlauf et al., 2005). In mouse models of MEN1, gastrin-expressing EGCs accumulate in the duodenum, and gastrinomas from patients with MEN1 express glial markers including GFAP and S100B (Sundaresan et al., 2017). These data highlight the possibility that gastrinomas in patients with MEN1 originate from duodenal EGCs.
Enteric Glia: The Origin of Duodenal Gastrinomas?
2017, GastroenterologySex-differences in [<sup>68</sup>Ga]Ga-DOTANOC biodistribution
2019, Nuclear Medicine and BiologyCitation Excerpt :Additionally, Rorsman et al. discussed that in diabetic patients the pancreatic islet cells excessively secrete somatostatin during hypoglycaemia [16] which also could influence [68Ga]Ga-DOTANOC uptake. Another paper linked the intake of PPIs to G-cell hyperplasia leading subsequently to hypergastrinemia [17] which is an established risk factor for the development of gastric NETs [18,19]. Currently, the role of gender is emerging in medicine.
Conflicts of interest Drs Grembecka and Cierpicki receive research support from Kura Oncology. They are also receiving compensation as members of the scientific advisory board of Kura Oncology, and have an equity ownership in the company. The remaining authors disclose no conflicts.
Funding R37 DK45729 (to J.L.M.) and Digestive Disease Center 5P30 DK034933; R01 CA160467 (to J.G.) and R01 CA200660 (to J.G.); R01 DK66604 (to M.J.L.); Molecular Core; UM Cancer Center P30 CA046592 Tissue and Transgenic Mouse Core.