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Pathophysiological mechanisms of peptides involved in the proliferation and differentiation of gastrointestinal mucosal epithelial cells.

肽参与胃肠粘膜上皮细胞增殖和分化的病理生理机制。

基本信息

批准号：
17590354
负责人：
ITOH Hiroshi
金额：
$ 2.24万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590354/
关键词：
HGF HGFA HAI H2RSP Gastrointestinal tract

项目摘要

Hepatocyte growth factor (HGF) has an important role in the proliferation and differentiation of gastrointestinal epithelial cells and is activated by a specific serine proteinase, namely HGF activator (HGFA). Activity of HGFA is strictly regulated by its specific inhibitors, HGFA inhibitors type-1 and-2 (HAM and HAI-2). HAI-2-related small peptide (H2RSP) is a recently identified small nuclear peptide and the gene consists of four exons spanning approximately 1 kbp and is located in 11 kbp downstream of HAI-2 gene. In this study, we developed a specific antibody against H2RSP and investigated the expression and localization of H2RSP in normal, injured and neoplastic human intestinal tissues. In the normal intestine, H2RSP was observed in the nuclei of surface epithelial cells and this nuclear localization was impaired in regenerating epithelium. In vitro, the nuclear translocation of H2RSP was observed along with increasing cellular density, and an over-expression of H2RSP resulted in … More a reduced growth rate. In well-differentiated colorectal adenocarcinomas, H2RSP expression was down-regulated. However, a significant up-regulation of the cytoplasmic H2RSP immunoreactivity was observed in cancer cells at the invasive front. These cells showed low MIB-1 labeling, an enhanced p16 expression and nuclear β-catenin. The number of H2RSP-positive cells in the invasive front of well-differentiated adenocarcinomas was significantly higher in the cases with lymph node metastases than node-negative ones. With the pull-down assay, no apparently bound nuclear proteins were detectable. On the other hand, recombinant H2RSP specifically bound to poly (rG) beads, but not to other polynucleotides, single or double strand DNA. Among several deleted series of recombinant H2RSP, only constructs containing exon 4 region bound to poly (rG). From these results, in the normal intestine, the nuclear accumulation of H2RSP is thought to a marker of differentiated epithelial cells. Although H2RSP was down-regulated in colorectal adenocarcinomas, a paradoxical up-regulation was observed in actively invading carcinoma cells. These H2RSP positive cells at the invasive front were considered to be low proliferating and invasive subpopulation. H2RSP immunoreactivity at the invasive front may serve as a marker of invasive phenotype of well-differentiated colon cancers. In order to investigate the relationship between HGF activation and H2RSP function, we also made several constructs of functional recombinant HGF-related molecules Less

肝细胞生长因子（HGF）在胃肠道上皮细胞的增殖和分化中具有重要作用，并被一种特异性丝氨酸蛋白酶激活，即HGF激活剂（HGFA）。HGFA的活性受其特异性抑制剂HGFA抑制剂1型和2型（HAM和HAI-2）的严格调节。HAI-2-related small peptide（H2 RSP）是新近发现的一种核小肽，该基因由4个外显子组成，长度约为1 kbp，位于HAI-2基因下游11 kbp处。在这项研究中，我们开发了一种针对H2 RSP的特异性抗体，并研究了H2 RSP在正常，损伤和肿瘤的人肠组织中的表达和定位。在正常肠中，H2 RSP被观察到在表面上皮细胞的细胞核中，并且这种核定位在再生上皮中受损。在体外，随着细胞密度的增加，沿着观察到H2 RSP的核转位，并且H2 RSP的过度表达导致细胞凋亡。 ...更多信息增长率下降。在高分化大肠腺癌中，H2 RSP表达下调。然而，一个显着的上调细胞质H2 RSP免疫反应性观察到癌细胞在浸润性前线。这些细胞显示低MIB-1标记，增强的p16表达和核β-catenin。高分化腺癌浸润前沿的H2 RSP阳性细胞数在有淋巴结转移的病例中显著高于无淋巴结转移的病例。用下拉试验，没有明显结合的核蛋白是可检测的。另一方面，重组H2 RSP特异性结合聚（rG）珠，但不结合其它多核苷酸、单链或双链DNA。在几个缺失的重组H2 RSP系列中，只有含有与poly（rG）结合的外显子4区域的构建体。根据这些结果，在正常肠中，H2 RSP的核积累被认为是分化的上皮细胞的标志物。虽然H2 RSP在结直肠腺癌中下调，但在积极侵袭的癌细胞中观察到矛盾的上调。这些位于浸润前沿的H2 RSP阳性细胞被认为是低增殖和浸润的亚群。H2 RSP在浸润前沿的免疫反应性可作为高分化结肠癌浸润表型的标志物。为了研究HGF活化和H2 RSP功能之间的关系，我们还构建了几种功能性重组HGF相关分子Less