Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

Int J Mol Sci. 2020 Jan 31;21(3):927. doi: 10.3390/ijms21030927.

Abstract

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Keywords: SPEM; acid inhibition; gastrin; netazepide; neuroendocrine cells.

MeSH terms

  • Animals
  • Benzodiazepinones / administration & dosage*
  • Benzodiazepinones / pharmacology
  • Exome Sequencing
  • Female
  • Gastric Mucosa / pathology*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / drug effects
  • H(+)-K(+)-Exchanging ATPase / genetics*
  • H(+)-K(+)-Exchanging ATPase / metabolism
  • Humans
  • Hyperplasia / prevention & control
  • In Situ Hybridization
  • Injections, Subcutaneous
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Metaplasia
  • Mice
  • Mice, Knockout
  • Neuroendocrine Cells / pathology*
  • Phenylurea Compounds / administration & dosage*
  • Phenylurea Compounds / pharmacology

Substances

  • Benzodiazepinones
  • Intercellular Signaling Peptides and Proteins
  • Phenylurea Compounds
  • spasmolytic polypeptide
  • H(+)-K(+)-Exchanging ATPase
  • YF 476