Abstract
Menin is the protein product of the Multiple Endocrine Neoplasia 1 (MEN1) gene locus at 11q13 and is a known tumor suppressor of neuroendocrine neoplasms (NENs). Gastrin-expressing NENs (gastrinomas) comprise the most frequent and malignant of the MEN1-dependent endocrine tumors. When gastrinomas are part of the MEN1 syndrome, they exhibit a greater propensity to develop within the submucosal Brunner’s glands of the duodenum. Therefore, models to analyze the biology of these intestinal gastrin-expressing NENs should consider their submucosal location.
Aim The goal of this study was to determine whether the Menin-MLL inhibitor MI-503 suppressed hypergastrinemia.
Methods A murine model of hypergastrinemia generated by omeprazole treatment of mice carrying a conditional deletion of Men1 bred onto a somatostatin null genetic background (OMS) was treated intraperitoneally with MI-503 for 1 month. Primary enteric glial cells were prepared from these OMS mice and were treated with increasing doses of MI-503. Similarly human AGS and mouse STC-1 gastrin producing cell lines were treated with EGF without or with MI-503.
>Results We found that the treatment reduced serum and gastro-duodenal tissue expression of gastrin. Ex vivo MI-503 treatment of glial fibrillary acidic protein (GFAP)+ enteric cells isolated from the OMS mice or gastrin-expressing cell lines revealed that MI-503 blocked the nuclear export of Menin and suppressed gastrin gene expression. RNA-Seq analysis of gastrin-treated GFAP+ enteric cells revealed that they express EGF receptor ligands and that EGF treatment of GFAP+ cells also induced Menin translocation and concurrent induction of gastrin gene expression.
Conclusion We concluded that MI-503 inhibits gastrin gene expression by blocking Menin translocation.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding: R01 DK45729 (to JLM) and Digestive Disease Center 5P30 DK034933; Molecular Core
Abbreviations
- Men1ΔIEC
- VillinCre;Men1FL/FL
- Sst-/-
- somatostatin null
- OMS
- Omeprazole-treated Men1ΔIEC;Sst-/-
- GFAP
- glial fibrillary acidic protein
- GAST
- gastrin