Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids

Sinju Sundaresan, Anthony J. Kang, Michael M. Hayes, Eun Young K. Choi, Juanita L. Merchant

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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 6â €..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 2â €..years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6â €..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.

Original languageEnglish (US)
Pages (from-to)1012-1021
Number of pages10
JournalGut
Volume66
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

  • ACID SECRETION
  • CANCER GENETICS
  • ENDOCRINE TUMOURS
  • GASTRIN
  • GASTRIN RECEPTORS

ASJC Scopus subject areas

  • Gastroenterology

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