|Budget Amount *help
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥10,600,000 (Direct Cost: ¥10,600,000)
Gastrin not only stimulates gastric acid secretion but also enhances gastric mucosal cell growth. Gastric mucosal atrophy due to H. pylori infection is often associated with hypergastrinemia, and moreover, gastric atrophy is believed to be a pre-cancerous state. Accordingly, hypergastrinemia has been considered to play some roles in the development of gastric cancer. Previously, we have first cloned human gastrin receptor gene, and found that it has poly T8 region in exon 5. In the present study, therefore, since poly T region is known to vulnerable to mutation in subjects with microsatellite instability(MSI), we examined whether or not gastrin gene mutation is found in gastric cancer tissues, and if so, such mutation is involved in the development of gastric cancer. The following results were obtained ;
(1) Mutation at polyT8 region of exon 5 of gastrin receptor gene was found in 6/16, 12/15 and 0/23 cases of gastric ECL caarcinoid tumors, gastric cancers with MSI and that without MSI,
(2) Expression of Reg protein, that is enhanced by gastrin stimulation, was observed in all the ECL carcinoid tumor with MSI, and 6/10 cases without MSI. On the other hand, in the MSI-positive gastric cancers, Reg protein expression was present in 10 of 12 cases with the receptor gene mutation and none of 3 cases without mutation. In contrast, Reg protein expression was detected in only 2 out of 23 cases of MSI-negative gastric cancers.
(3) NIH3T3 cells transfected with either T6 or T7 mutation of gastrin receptor gene showed enhanced proliferative activity under basal condition without gastrin administration. In contrast, gastrin had any effect on neither intracellular calcium elevation in nor growth of NIH3T3 cells transfected the mutated gastrin receptor cDNA, whereas gastrin enhanced both calcium elevation and growth of the cells transfected with normal gastrin receptor cDNA. From these data, it is concluded that the mutation at poly T8 region of exon 5 of gastrin receptor gene is frequently found in gastric ECL carcinoid tumor as well as gastrin cancer tissues with MSI. This mutation may play roles in the enhanced expression of Reg protein in the tumor cells and also their tumorigenesis, Less