Sonic hedgehog in gastric physiology and neoplastic transformation: friend or foe?

Abstract

Purpose of review: To understand the role of sonic hedgehog (Shh) in normal gastric physiology and neoplastic transformation.

Recent findings: Emerging evidence shows that gastric epithelial cells produce Shh ligand, which subsequently targets the mesenchyme. This paracrine signaling event is recapitulated by Shh-producing tumors that signal to the supporting stroma to encourage growth. Primary cilia contain components of the hedgehog signaling apparatus, and thus are typically found on responding stromal cells.

Summary: In the stomach, Shh is produced in epithelial cells and received by responding cells in the mesenchyme. In vitro, Shh enhances gastric acid secretion and induces mucin expression. It remains to be determined whether the canonical signaling pathway mediates the observed epithelial effects. Shh expression and signaling is reduced in chronic gastritis, and Shh(-/-) embryos exhibit hyperplasia and metaplastic changes in the gastric mucosa. After its loss in the corpus, Shh is re-expressed in some gastric carcinomas typically arising in the distal stomach or antrum, suggesting that it promotes tumor growth.

Figure 1. Shh and H⁺/K⁺-ATPase co-translocate to the apical membrane of parietal cells upon stimulation of acid secretion

A). Co-translocation of Shh (green) and H⁺/K⁺-ATPase (red) to the apical membrane of parietal cells upon stimulation of gastric acid secretion. Mouse parietal cells were identified in gastric primary cultures by H⁺/K⁺-ATPase staining, and compared with and without stimulation by 100µM histamine and 100µM isobutylmethylxanthine (IBMX). Fluorescent staining was visualized by confocal microscopy. Top left panel: Shh protein (green); bottom left panel: H⁺/K⁺-ATPase protein (red); top right panel: merge (yellow); bottom right panel: differential interference contrast (DIC) microscopy. B). Western blot of tubulovesicle (TV), plasma membrane (Pl Mem), and mitochondrial (Mito) fractions demonstrating co-translocation of H⁺/K⁺-ATPase and Shh proteins upon stimulation with histamine (His) versus cimetidine (Cim) in canine parietal cells. H⁺/K⁺-ATPase and Shh proteins decrease in P3 (TV fraction) but increase in P1 (plasma membrane fraction) upon stimulation with histamine. Different sizes of the processed Shh protein (45kDa, 37kDa and 15kDa) are annotated. The plasma membrane and tubulovesicle fractions were obtained by centrifugation through a 12% – 18% Ficoll 400 density step gradient and a 40% - 35% -10% sucrose gradient respectively.

Figure 1. Shh and H⁺/K⁺-ATPase co-translocate to the apical membrane of parietal cells upon stimulation of acid secretion

A). Co-translocation of Shh (green) and H⁺/K⁺-ATPase (red) to the apical membrane of parietal cells upon stimulation of gastric acid secretion. Mouse parietal cells were identified in gastric primary cultures by H⁺/K⁺-ATPase staining, and compared with and without stimulation by 100µM histamine and 100µM isobutylmethylxanthine (IBMX). Fluorescent staining was visualized by confocal microscopy. Top left panel: Shh protein (green); bottom left panel: H⁺/K⁺-ATPase protein (red); top right panel: merge (yellow); bottom right panel: differential interference contrast (DIC) microscopy. B). Western blot of tubulovesicle (TV), plasma membrane (Pl Mem), and mitochondrial (Mito) fractions demonstrating co-translocation of H⁺/K⁺-ATPase and Shh proteins upon stimulation with histamine (His) versus cimetidine (Cim) in canine parietal cells. H⁺/K⁺-ATPase and Shh proteins decrease in P3 (TV fraction) but increase in P1 (plasma membrane fraction) upon stimulation with histamine. Different sizes of the processed Shh protein (45kDa, 37kDa and 15kDa) are annotated. The plasma membrane and tubulovesicle fractions were obtained by centrifugation through a 12% – 18% Ficoll 400 density step gradient and a 40% - 35% -10% sucrose gradient respectively.