Aberrant expression of TTF-1 and forkhead factor HFH-4 in atrophic gastritis and ciliated metaplasia suggests gastric broncho-pulmonary transdetermination.

Ciliated metaplasia (CM) in the stomach is mainly found in gastric mucosa that harbours gastric cancer. The true nature of this lesion and the regulatory factors responsible for the formation of CM are unknown. Broncho-pulmonary differentiation is controlled by the homeodomain transcription factor TTF-1 and ciliogenesis by the forkhead transcription factor HFH-4, respectively. Using immunohistochemistry, the present study shows that gastric CM is associated with the expression of TTF-1 and HFH-4. Furthermore, TTF-1 expression was found in non-ciliated cells in 50% of cases with atrophic gastritis, whereas TTF-1 and HFH-4 were not expressed in normal gastric mucosa or in non-atrophic gastritis. These data suggest that CM in the gastric mucosa can be regarded as gastric broncho-pulmonary transdetermination. Evidence for this particular transdetermination is frequently found in atrophic gastritis even without fully developed ciliated cells.

Transcription of sonic hedgehog, a potential factor for gastric morphogenesis and gastric mucosa maintenance, is up-regulated in acidic conditions.

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.