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


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.

  • Source
    • "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). "

    Full-text · Chapter · Aug 2011
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oestrogen receptor-alpha (ERalpha) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERalpha-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear. We used 17-beta-oestradiol (E2) as a stimulator against the ERalpha pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERalpha (ERalpha siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERalpha-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined. In ERalpha-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-beta-Oestradiol-induced cell proliferation was suppressed by ICI, ERalpha siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERalpha siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERalpha and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERalpha and Hh pathways. Our data indicate that activation of the ERalpha pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERalpha-positive gastric cancer.
    Preview · Article · Feb 2010 · British Journal of Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastric cancer (GC) remains one of the most common cancers worldwide. Its prevalence is still on the rise in the developing countries due to the ageing population. The cancer stem cell (CSC) theory provides a new insight into the interpretation of tumor initiation, aggressive growth, recurrence, and metastasis of cancer, as well as the development of new strategies for cancer treatment. This review will focus on the progress of biomarkers and signaling pathways of CSCs, the complex crosstalk networks between the microenvironment and CSCs, and the development of therapeutic approaches against CSCs, predominantly focusing on GC.
    No preview · Article · Jul 2012 · Journal of Gastroenterology
Show more