权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of angiogenesis by PEDF, anti-angiogenic factor, for controlling Oral Diseases

通过 PEDF（抗血管生成因子）调节血管生成，以控制口腔疾病

基本信息

批准号：
15390558
负责人：
MORITA Ikuo
金额：
$ 9.54万
依托单位：
TOKYO MEDICAL AND DENTAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390558/
关键词：
Angiogenesis PEDF VEGF oral squamous cell carcinoma collagen-binding site age-related macular degeneration 血管新生抑制アミロイドβ 血管内皮細胞 PFDF VEGF 老化扁平上皮ガン

项目摘要

The objectives in this study are to regulate oral cancer and to establish the method for repair in oral function by controlling angiogenesis. In this research, we examined the regulation mechanism for PEDF production and the molecular mechanism for anti-angiogenic activity of PEDF. When the human oral squamous cell carcinoma cell lines were exposed by ischemia, PEDF production was up-regulated, in contrast, PEDF was down-regulated by ischemia in normal cells. In ischemia, VEGF was up-regulated and this VEGF stimulated PEDF production via PEDFR-1. It is interesting that PEDF/VEGF ratio increased in benign tumor, but decreased dramatically in cancer. These results suggest that in cancer the low PEDF/VEGF ratio causes to angiogenesis in cancer tissue, and the part of angiogenesis is escaped from ischemia, which leads to decrease PEDF production. Next, we investigated here the possibility the involvement of the motif for ECM interaction in anti-angiogenic activity of PEDF. The growth rates of HeLa cells in culture were not affected by transfection of PEDF, indicating that PEDF did not suppress tumor cell growth directly. In tumor xenografts, overexpression of wild-type PEDF significantly suppressed tumor growth, whereas the mutant of collagen I-binding site of PEDF (Col-mut PEDF) did not inhibit tumor growth. The mutant of heparin-binding site of PEDF (Hep-mut PEDF) suppressed tumor growth. Histological analysis showed that the density and area of microvasculatures in either PEDF or Hep-mut PEDF were suppressed as compared with those in either vector or Col-mut PEDF. Our data indicate that PEDF inhibits tumor growth via anti-angiogenic activity, and the collagen I -binding motif of PEDF is involved in the biological activity. We also examined the cloning of PEDF receptor using by expression cloning technique. We got several genes to bind for PEDF, and we have examined whether these proteins was a receptor for PEDF.

本研究的目的是通过控制血管生成来调控口腔癌，建立口腔功能修复的方法。在本研究中，我们研究了PEDF产生的调节机制和PEDF抗血管生成活性的分子机制。人口腔鳞状细胞癌细胞系经缺血处理后，PEDF表达上调，而正常细胞经缺血处理后PEDF表达下调。在缺血时，VEGF上调，并且这种VEGF通过PEDFR-1刺激PEDF产生。值得注意的是，PEDF/VEGF比值在良性肿瘤中升高，而在恶性肿瘤中显著降低。这些结果表明，在癌症中，低PEDF/VEGF比率导致癌组织中的血管生成，并且部分血管生成从缺血中逃逸，这导致PEDF产生减少。接下来，我们研究了ECM相互作用的基序参与PEDF抗血管生成活性的可能性。HeLa细胞在培养中的生长速率不受PEDF转染的影响，表明PEDF不直接抑制肿瘤细胞的生长。在肿瘤异种移植物中，野生型PEDF的过度表达显著抑制肿瘤生长，而PEDF的胶原I结合位点的突变体（Col-mut PEDF）不抑制肿瘤生长。PEDF肝素结合位点突变体（Hep-mut PEDF）抑制肿瘤生长。组织学分析显示，与载体或Col-mut PEDF相比，PEDF或Hep-mut PEDF中的微血管密度和面积受到抑制。我们的数据表明，PEDF通过抗血管生成活性抑制肿瘤生长，PEDF的I型胶原结合基序参与生物活性。我们还利用表达克隆技术研究了PEDF受体的克隆。我们得到了几个与PEDF结合的基因，我们已经检查了这些蛋白质是否是PEDF的受体。