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: 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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Authors | Sinju Sundaresan, Anthony J Kang, Michael M Hayes, Eun-Young K Choi, Juanita L Merchant |
Journal | Gut
(Gut)
Vol. 66
Issue 6
Pg. 1012-1021
(06 2017)
ISSN: 1468-3288 [Electronic] England |
PMID | 26860771
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. |
Chemical References |
- 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
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Topics |
- Adenocarcinoma
(metabolism)
- Adult
- Animals
- Benzodiazepines
(pharmacology)
- Carcinogenesis
(drug effects, genetics)
- Carcinoid Tumor
(genetics)
- Cell Line, Tumor
- Cyclin-Dependent Kinase Inhibitor p27
(metabolism)
- Female
- Gastrins
(blood, genetics, metabolism, 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, metabolism)
- Signal Transduction
- Somatostatin
(genetics)
- Stomach Neoplasms
(genetics, metabolism)
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