Transcription of Sonic Hedgehog, a Potential Factor for Gastric Morphogenesis and Gastric Mucosa Maintenance, Is Up-regulated in Acidic Conditions

Institute of Pathology, University of Erlangen-Nuremberg, Erlangen, Germany.
Laboratory Investigation (Impact Factor: 3.68). 01/2004; 83(12):1829-37. DOI: 10.1097/01.LAB.0000101729.25140.0C
Source: PubMed

ABSTRACT Gastric body mucosa atrophy predisposes one to gastric cancer. Disturbances in the gastric differentiation process might play a role in the evolution of gastric atrophy. Sonic hedgehog (Shh) has recently been implicated as a crucial factor in gastric organogenesis and gland differentiation. In this study we investigated the expression of key factors in the Shh pathway, namely Shh and its receptor Patched (Ptc), in normal and pathologic stomach mucosa. Furthermore, the potential role of pH for Shh dysregulation was analyzed. Ten gastric biopsy specimens each from normal gastric mucosa, chronic nonatrophic gastritis, atrophic gastritis, and gastric cancer were included. Expression of Shh and Ptc was analyzed by immunohistochemistry. In normal body mucosa and in nonatrophic body gastritis, Shh was strongly expressed in parietal cells. Ptc was also expressed in gastric chief cells. Shh expression was almost completely lost in atrophic gastritis and in gastric cancer and absent in intestinal metaplasia. Ptc was markedly reduced in atrophy and only weakly positive in intestinal metaplasia and gastric cancer. In in vitro experiments, gastric cancer cell line 23132 was found positive for Shh. In long-term culture as well as in culture conditions with low pH, transcription of Shh in 23132 was significantly increased in quantitative reverse transcription PCR analyses. We concluded that the decreased expression of the Shh pathway in atrophic gastritis and gastric cancer might reflect altered differentiation processes within the gastric unit and contributes to the development of gastric atrophy. The increase of gastric pH might play a role in the development of gastric mucosa atrophy via reduction of Shh transcription.

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    • "Since stomach secretes numerous factors such as TGFβ, Wnt, FGFs and including Hedgehog proteins that are responsible for the differentiation of the gastric epithelium, one favored explanation linking inflammation and progression to cancer is due to the loss of Hedgehog as result parietal cell atrophy (reviewed in (Katoh & Katoh, 2006)). In conditions such as gastric atrophy and intestinal metaplasia, where normal gastric morphogenesis is lost, Shh is reduced or absent (Dimmler et al., 2003; Shiotani et al., 2005a; Shiotani et al., 2005b; Suzuki et al., 2005; van den Brink et al., 2002; Van Den Brink et al., 2001). In support of this, in Mongolian gerbils infected with H. pylori loss of Shh expression correlates with loss of parietal cells, impaired maturation of the zymogenic chief cells in gastric glands, and intestinal metaplasia (Suzuki et al., 2005). "
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    • "The hedgehog (Hh) signalling pathway has a crucial role in embryonic development, tissue regeneration and carcinogenesis. Of the three Hh ligands, namely Sonic Hh (Shh), Indian Hh (Ihh) and Desert Hh (Dhh) (Pasca di Magliano and Hebrok, 2003; Lum and Beachy, 2004; Briscoe and Therond, 2005; Hooper and Scott, 2005; Katoh and Katoh, 2005), Shh is exclusively expressed in the acidproducing parietal cells in both human and murine stomach, and is believed to be a regulator of gastric fundic gland differentiation and mutation (Ramalho-Santos et al, 2000; van den Brink et al, 2001, 2002; Dimmler et al, 2003). Pharmacological inhibition of Shh signalling in the adult stomach causes loss of parietal cells (gastric atrophy) and subsequent disruption of glandular differentiation (van den Brink et al, 2002). "
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