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Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids
  1. Sinju Sundaresan1,
  2. Anthony J Kang1,
  3. Michael M Hayes1,
  4. Eun-Young K Choi2,
  5. Juanita L Merchant1,3
  1. 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  2. 2Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Juanita L Merchant, Department of Internal Medicine, University of Michigan, Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; merchanj{at}


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.


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