Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids

Gut. 2017 Jun;66(6):1012-1021. doi: 10.1136/gutjnl-2015-310928. Epub 2016 Feb 9.


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 p27Kip1 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 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.

Conclusions: Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27Kip1 cellular location and stability.


Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adult
  • Animals
  • Benzodiazepines / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinoid Tumor / genetics*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Female
  • Gastrins / blood
  • Gastrins / genetics
  • Gastrins / metabolism*
  • Gastrins / pharmacology
  • Gene Deletion
  • Hormone Antagonists / pharmacology
  • Hormones / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Omeprazole / pharmacology
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / genetics*
  • Proton Pump Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Receptor, Cholecystokinin B / genetics
  • Receptor, Cholecystokinin B / metabolism
  • Signal Transduction
  • Somatostatin / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism*


  • Gastrins
  • Hormone Antagonists
  • Hormones
  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • Proton Pump Inhibitors
  • RNA, Messenger
  • Receptor, Cholecystokinin B
  • Benzodiazepines
  • YM 022
  • Cyclin-Dependent Kinase Inhibitor p27
  • Somatostatin
  • Omeprazole