Role of REG protein in gastric cell proliferation, in vitro and in vivo.

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Reg (regenerating gene product) was originally identified as a growth factor involved in pancreatic regeneration. During the healing course of gastric erosion, Reg expression is highly increased in the enterochromaffin-like (ECL) cells surrounding the ulcer crater, suggesting its role as a regulator of gastric mucosal regeneration. To date, there has been no information available on Reg mediated intracellular signal transduction pathways. The role of Reg in the gastric carcinogenesis is also unknown. Furthermore, there has been no direct in vivo evidence of a growth promoting-role of Reg for the gastric mucosal cells.In the current study, the Reg signaling pathway in gastric cancer cell was examined. Reg treatment of MKN45 gastric cancer cells resulted in tyrosyl-phoshorylation of several cellular proteins and subsequent activation of classical MAPK, ERK1/2. Reg also stimulated thymidine incorporation in MKN45 and AGS gastric cancer cells in a dose dependent manner. Finally, Reg was sh … More own to be, highly expressed in a large number of gastric cancers in vivo. Taken together, these data suggest that gastric cancer cells have gained the ability to overexpress Reg protein, which confer upon themselves added proliferative capacities, resulting in a considerable growth advantage.REG-transgenic mice were created and gastric mucosa were analyzed for histological changes. Transgenic mice showed a marked increase in the thickness of the fundic mucosa. Anti-proliferating cell nuclear antigen (PCNA) staining of the fundic mucosa demonstrated the enlargement of the proliferating neck zone and the lower PCNA-negative zone. Histological analysis employing antibodies against cell-type markers revealed expansion of the chief cell and parietal cell populations and no change in the number of surface mucus producing cells, ECL cells, or G cells. In conclusion, Reg has a growth promoting effect on gastric progenitor cells and an activity to direct the differentiation of the cells into chief cell and parietal cell lineages. This was in, contrast to other factors, all of which had been shown,to drive differentiation towards mucus producing cells in vivo. In the injured gastric mucosa, Reg may play a unique and important part in the reconstruction of the properly organized mucosal architecture. Less