A ROLE OF GASTRIN RECEPTOR GENE MUTATION IN THE DEVELOPMENT OF GASTRIC CANCER

胃泌素不仅能刺激胃酸分泌，还能促进胃粘膜细胞生长。幽门螺杆菌感染引起的胃粘膜萎缩通常与高胃泌素血症有关，而且，胃萎缩被认为是癌前状态。因此，高胃泌素血症被认为在胃癌的发生发展中起一定作用。此前，我们首次克隆了人胃泌素受体基因，并发现其在外显子5中具有多聚T8区。因此，鉴于微卫星不稳定性(MSI)受试者中多聚T区易发生突变，本研究检测了胃癌组织中是否存在胃泌素基因突变，如果是，这种突变与胃癌的发生有关。结果发现：(1)胃泌素受体基因第5外显子多聚T8区突变分别发生在6/16、12/15和0/23例胃上皮样癌、伴微囊癌和不伴微囊癌、…的胃癌中(2)所有伴有MSI的ECL类癌和6/10例无MSI的ECL类癌均可见胃泌素刺激增强的Reg蛋白表达。而在MSI阳性的胃癌中，受体基因突变的12例中有10例表达REG蛋白，3例无突变的胃癌中无一例表达REG。23例MSI阴性胃癌中仅2例检测到Reg蛋白表达。(3)未加胃泌素的NIH3T3细胞在基础培养条件下，胃泌素受体基因T6或T7突变的NIH3T3细胞的增殖活性增强。反之，胃泌素对转导突变胃泌素受体基因的NIH3T3细胞内钙离子浓度升高和细胞生长均无影响，而胃泌素促进正常胃泌素受体基因转染组细胞内钙离子浓度升高和生长。结果表明，胃泌素受体基因外显子5的多聚T8区突变在胃ECL类癌和胃泌素癌组织中是常见的。这种突变可能在肿瘤细胞中REG蛋白的表达增强以及肿瘤的发生中起作用，而不是

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, … More respectively.(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