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黏膜萎缩常伴有高胃泌素血症，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，发现其在第5外显子有多聚T8区。因此，在本研究中，由于已知多T区在微卫星不稳定性（microsatellite instability， MSI）受试者中易发生突变，我们研究了胃泌素基因在胃癌组织中是否存在突变，如果存在，这种突变是否参与了胃癌的发生。得到以下结果：(1)胃泌素受体基因5外显子polyT8区突变分别发生在6/16、12/15和0/23例胃ECL类癌、伴MSI胃癌和无MSI胃癌中。(2)所有伴有MSI的ECL类癌和6/10无MSI的ECL类癌均表达Reg蛋白，且胃泌素刺激后Reg蛋白表达增强。另一方面，在msi阳性胃癌中，受体基因突变的12例中有10例有Reg蛋白表达，未突变的3例中无Reg蛋白表达。相比之下，23例msi阴性胃癌中只有2例检测到Reg蛋白表达。(3)转染胃泌素受体基因T6或T7突变的NIH3T3细胞在无胃泌素的基础条件下增殖活性增强。相比之下，胃泌素对转染突变胃泌素受体cDNA的NIH3T3细胞的细胞内钙升高和生长均无影响，而转染正常胃泌素受体cDNA的NIH3T3细胞内钙升高和生长均有促进作用。综上所述，胃泌素受体基因5外显子poly T8区域的突变在胃ECL类癌以及伴有MSI的胃泌素癌组织中较为常见。该突变可能与肿瘤细胞中Reg蛋白的表达增强及肿瘤发生有关

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