Reduced Shh expression in TFF2-overexpressing lesions of the gastric fundus under hypochlorhydric conditions

Y. Minegishi, H. Suzuki, M. Arakawa, Y. Fukushima, T. Masaoka, T. Ishikawa, N. A. Wright, T. Hibi

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Abstract

Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H2 receptor-knockout (H2R-null) mice and an acid exposure model. Age-matched H2R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H2R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H 2R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis.

Original languageEnglish
Pages (from-to)161-169
Number of pages9
JournalJournal of Pathology
Volume213
Issue number2
DOIs
Publication statusPublished - 2007 Oct 1

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Keywords

  • Gastric acid
  • Morphogen
  • Parietal cell
  • Sonic hedgehog
  • Zymogenic cell

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Minegishi, Y., Suzuki, H., Arakawa, M., Fukushima, Y., Masaoka, T., Ishikawa, T., Wright, N. A., & Hibi, T. (2007). Reduced Shh expression in TFF2-overexpressing lesions of the gastric fundus under hypochlorhydric conditions. Journal of Pathology, 213(2), 161-169. https://doi.org/10.1002/path.2221