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

REG 蛋白在体外和体内胃细胞增殖中的作用。

• 批准号: 14570471
• 负责人: KADOWAKI Yasunori
• 金额: $ 2.3万
• 依托单位: Shimane University (Faculty of Medicine)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570471/
• 关键词: Reg; gastric cancer; tyrosine kinase; ERK1; 2; transgenic mice; carcinogenesis; REG; トランスジェニックマウス; ノックアウトマウス; 胃癌; 増殖因子; 潰瘍治癒過程

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

Reg（再生基因产物）最初被鉴定为参与胰腺再生的生长因子。在胃糜烂的愈合过程中，Reg在溃疡口周围的肠嗜铬样（ECL）细胞中的表达高度增加，表明其作为胃粘膜再生的调节剂的作用。迄今为止，还没有关于Reg介导的细胞内信号转导途径的信息。Reg在胃癌发生中的作用也是未知的。此外，目前还没有直接的体内证据表明Reg对胃粘膜细胞的生长有促进作用。Reg处理MKN 45胃癌细胞导致几种细胞蛋白质的酪氨酰磷酸化和随后的经典MAPK，ERK 1/2的激活。Reg还以剂量依赖性方式刺激MKN 45和AGS胃癌细胞中的胸苷掺入。最后，雷格是sh ...更多信息 在体内大量胃癌中高度表达。总之，这些数据表明，胃癌细胞已经获得了过度表达Reg蛋白的能力，这赋予了它们自身额外的增殖能力，从而产生了相当大的生长优势。转基因小鼠的胃底粘膜厚度明显增加。胃底粘膜的抗增殖细胞核抗原（PCNA）染色显示增殖颈区和较低的PCNA阴性区扩大。采用抗细胞类型标记物抗体的组织学分析显示主细胞和壁细胞群的扩增，并且表面粘液产生细胞、ECL细胞或G细胞的数量没有变化。总之，Reg对胃前体细胞具有生长促进作用，并具有指导细胞分化为主细胞和壁细胞谱系的活性。这与其他因素相反，所有这些因素都已被证明在体内驱动向粘液产生细胞的分化。在损伤的胃粘膜中，Reg可能在正常组织的粘膜结构重建中发挥独特而重要的作用。少

项目成果

Yuki T, et al.: "Expression of midkine and receptor-like protein tyrosine phosphatase(RPTP)-beta genes in the rat stomach and the influence of rebamipide."Aliment Pharmacol Ther.. 18. 106-112 (2003)

Yuki T 等人：“大鼠胃中中期因子和受体样蛋白酪氨酸磷酸酶 (RPTP)-β 基因的表达以及瑞巴派特的影响。”Aliment Pharmacol Ther. 18. 106-112 (2003)

Kazumori H, et al.: "Transforming growth factor-alpha directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin-like cells."Am J Physiol Gastrointest Liver Physiol. 286. G503-G514 (2004)

Kazumori H 等人：“转化生长因子-α 直接增强大鼠肠嗜铬样细胞中组氨酸脱羧酶和囊泡单胺转运蛋白 2 的产生。”Am J Physiol Gastrointest Liver Physiol。

Y.Miyaoka, et al.: "Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages."Oncogene. (in press).

Y.Miyaoka 等人：“Reg 蛋白的转基因过度表达导致胃细胞沿壁细胞和主细胞谱系增殖和分化。”癌基因。

Toshihiko Okuyama, et al.: "Activation of prostaglandin E2 receptor EP2 and EP4 pathways"J.Lab.Clin.Med.. 140. 92-102 (2002)

Toshihiko Okuyama 等：“前列腺素 E2 受体 EP2 和 EP4 途径的激活”J.Lab.Clin.Med.. 140. 92-102 (2002)

Toshihiko Okuyama, et al.: "Activation of prostaglandin E2 receptor EP2 and EP4 pathways induces growth inhibition in human gastric carcinoma cell lines."J.Lab.Clin.Med.. 140. 92-102 (2002)

Toshihiko Okuyama 等人：“前列腺素 E2 受体 EP2 和 EP4 途径的激活可诱导人胃癌细胞系的生长抑制。”J.Lab.Clin.Med.. 140. 92-102 (2002)