Deletion ofMen1andsomatostatininduces hypergastrinemia and gastric carcinoids

Abstract

Gastric carcinoids are slow growing neuroendocrine tumors arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumors arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumors. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal. Objective To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines. Design: The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27Kip1 was tested on the human AGSE and mouse STC-1 cell lines. Results The combination of conditional Men1 deletion in the absence of somatostatin lead to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27Kip1 both in vivo and in gastrin-treated cell lines. Loss of p27Kip1 was also observed in human gastric carcinoids arising in the setting of atrophic gastritis. Conclusion Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27Kip1 cellular location and stability.

The future: genetics advances in MEN1 therapeutic approaches and management strategies

“…Also, knockout of Men1 in the liver (using albumin promoter/ALB-Cre), a tissue not targeted in MEN1, does not lead to tumors in the liver despite the complete loss of Men1 (Scacheri, et al 2004). Other mouse models with knockout of Men1 in pancreatic endocrine cell lineages, bone cells, and intestinal cells have also helped to gain insight into the physiological actions of menin (Bonnavion, et al 2015; Kanazawa, et al 2015; Liu, et al 2017; Sundaresan, et al 2016; Veniaminova, et al 2012). These elegant studies in genetically engineered mouse models show that menin may function as a cell-type-specific tumor suppressor, and that its action is only required in MEN1-associated target tissues to prevent tumorigenesis.…”

Gastrin-induced miR-222 promotes gastric tumor development by suppressing p27kip1

“…This was associated with alterations in p27 phosphorylation with increases in P-p27 Thr187 , P-p27 Ser10 and P-p27Kip1 Thr198 being observed. Moreover this paper also reported loss of p27 expression in human type 1 gastric neuroendocrine tumors associated with atrophic gastritis and showed similar alterations in p27 distribution (by immunocytofluorescence as well as subcellular fractionation) in the CCK2R expressing AGS-E cell line following gastrin treatment [59]. …”

“…Long-term exposure to H. pylori in animal [56] and cell culture [57] models has also been shown to promote an apoptosis-resistant phenotype associated with decreased p27 expression [58]. A very recent paper has also demonstrated reduced p27 expression in gastric carcinoid tumors arising in transgenic mice that was hypergastrinemic as a result of deletion of Men1 and somatostatin along with treatment with omeprazole [59]. This was associated with alterations in p27 phosphorylation with increases in P-p27 Thr187 , P-p27 Ser10 and P-p27Kip1 Thr198 being observed.…”

Pathophysiology of Gastric NETs: Role of Gastrin and Menin

“…We previously showed that somatostatin stimulates menin expression in vitro and that both are known inhibitors of gastrin gene expression and secretion. Recently, we reported that conditional deletion of the Men1 locus on a somatostatin (Sst) null background ( Villin-Cre: Men1 FL/FL ; Sst −/− ) generated carcinoid hyperplasia and tumors in the corpus that infiltrated the submucosa and smooth muscle layer representing the first genetically engineered mouse model for gastric carcinoid tumors (34). Treatment of these mice with the acid suppressing proton pump inhibitor (PPI), omeprazole accelerated the occurrence of these tumors, which within 6 months of beginning acid suppression with omeprazole (34).…”