| First Author | Sundaresan S | Year | 2017 |
| Journal | Gut | Volume | 66 |
| Issue | 6 | Pages | 1012-1021 |
| PubMed ID | 26860771 | Mgi Jnum | J:355479 |
| Mgi Id | MGI:7748845 | Doi | 10.1136/gutjnl-2015-310928 |
| Citation | Sundaresan S, et al. (2017) Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids. Gut 66(6):1012-1021 |
| abstractText | BACKGROUND: Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. 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 p27(Kip1) was tested on the human human gastric adenocarcinoma cell line stably expressing CCKBR (AGSE) and mouse small intestinal neuroendocrine carcinoma (STC)-1 cell lines. RESULTS: The combination of conditional Men1 deletion in the absence of somatostatin led 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 p27(Kip1) both in vivo and in gastrin-treated cell lines. Loss of p27(Kip1) was also observed in human gastric carcinoids arising in the setting of atrophic gastritis. CONCLUSIONS: Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27(Kip1) cellular location and stability. |
