The new approach of radiotherapy for the prevention of metastasis

预防转移的放射治疗新方法

基本信息

批准号：
09670947
负责人：
HAREYAMA Masato
金额：
$ 1.92万
依托单位：
SAPPORO MEDICAL UNIVERSITY, SCHOOL 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：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670947/
关键词：
radiotherapy metastasis JNK BAG-1 apoptosis radiation sensitivity ICAM-1 c-erb B-2 Bcl-2 IFN-gamma IL-3

项目摘要

1. A Bcl-2-binding protein BAG-1 is identified as an anti-apoptotic molecule and binds to Raf-1, Hsp7O/Hsc7O, steroid hormone and hepatocyte growth factor (HGF) receptors, implicating multifunctions of BAG-1. In order to explore a method for suppression of cancer metastasis by irradiation, we establish an animal model which modulates metastasis potential of gastric cancer cells by overexpression of BAG-1 or Bcl-2. Namely, overexpression of BAG-1 in human gastric cancer cells led to prolonged cell survival against anoikis and increased peritoneal dissemination. In addition, we demonstrate that overexpression of BAG-1 strongly enhances the motility of human gastric cancer cells. In the gastric cancer MKN74 cells overexpression BAG-1, BAG1 colocalized with cytokeratin, and was concentrated at membrane ruffles induced by lysophosphatidic acid (LPA), resulting in partial colocalization with actin. These data strongly suggest cooperative roles of BAG-1 in the functions of epithelial cell cyt … More oskeletal proteins. Two independent migration assays showed that the BAG-1-expressing MKN74 cells exhibited strong enhancement of their migration compared with the control transfectants or parent MKN74 cells. In MKN74 cells, the overexpression of BAG-1 affected neither cell adhesion capability nor response to HGF.The promotive effect of BAG-1 on cell migration was similarly observed in transfectants of another human gastric cancer MKN45 cell line. Taken together, these studies demonstrate that BAG-1 is a good candidate as a target molecule for suppression of gastric cancer metastasis.2. We have also investigated several possible factors for determining apoptosis sensitivity to irradiation. By investigating JNK activity in more than 20 human cancer cell lines after irradiation, we found a tight correlation between an increase of JNK activity and sensitivity to irradiation-induced apoptosis.3. We have investigated the effect of irradiation on the surface antigen expression of proto-oncogene c-erb B-2 and intercellular adhesion molecule-1 (ICAM-l) on human adenocarcinoma cell lines. The expression ofthe Erb B-2 protein and ICAM-l on the cell membrane was found to increase by irradiation. The results suggest that the low dose radiation may be useful for accumulating LFA-1 positive cytotoxic T lymphocytes (CTL) at the local tumor tissue, which tumor cells may be attacked. Less

1。Bcl-2结合蛋白BAG-1被鉴定为抗凋亡分子，并与RAF-1，HSP7O/HSC7O，类固醇骑马酮和肝细胞生长因子（HGF）受体结合，暗示了BAG-1的多功能。为了探索一种通过辐射抑制癌症转移的方法，我们建立了一种动物模型，该模型通过BAG-1或BCL-2的过表达来调节胃癌细胞的转移潜力。也就是说，人类胃癌细胞中BAG-1的过表达导致对厌氧菌的长时间存活和腹膜传播增加。此外，我们证明BAG-1的过表达强烈增强了人类胃癌细胞的运动。在胃癌MKN74细胞中过表达的BAG-1，BAG1与细胞角蛋白共定位，并集中在溶血磷脂酸（LPA）诱导的膜褶皱上，导致与肌动蛋白部分共定位。这些数据强烈暗示了Bag-1在上皮细胞细胞的功能中的辅导作用…更多的骨骼蛋白。两种独立的迁移测定表明，与对照转化体或亲本MKN74细胞相比，表达BAG-1的MKN74细胞的迁移表现出强烈的增强。在MKN74细胞中，BAG-1的过表达既不会影响细胞粘附能力，也没有影响对HGF的反应。在另一种人胃癌MKN45细胞系的翻译中类似地观察到了Bag-1对细胞迁移的促进作用。综上所述，这些研究表明，BAG-1是抑制胃癌转移的靶标分子的好候选者。2。我们还研究了确定凋亡对辐照敏感性的几个可能因素。通过在辐射后研究JNK活性，在20多个人类癌细胞系中，我们发现JNK活性的增加与对辐照诱导的凋亡的敏感性之间存在密切的相关性。3。我们已经研究了辐射对原始癌基因C-ERB B-2和细胞间粘附分子1（ICAM-L）表面抗原表达的影响。发现ERB B-2蛋白和ICAM-L在细胞膜上的表达通过辐照增加。结果表明，低剂量辐射可能有助于累积局部肿瘤组织的LFA-1阳性细胞毒性T淋巴细胞（CTL），该肿瘤细胞可能会受到攻击。较少的