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Regulation of adhesion molecule integrins by membrane-bound proteinase ADAM

膜结合蛋白酶 ADAM 对粘附分子整合素的调节

基本信息

批准号：
16390117
负责人：
MATSUURA Nariaki
金额：
$ 9.54万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390117/
关键词：
ADAM integrin cancer metastasis metalloproteinase disintegrin )ディスインテグリン脳転移肺癌

项目摘要

ADAM is membrane-bound molecules composed of metalloproteinase and disintegrin. Expression of ADAM molecules of highly brain-metastatic subline and bone-metastatic subline from lung cancer cell EBC-1 cells are studied in order to clarify the implication of ADAM in cancer metastasis. As a result the expression level of ADAM9 mRNA was upregulated in brain-metastatic subline than those in bone-metastatic subline or parental cell line. Transfection of ADAM9 cDNA in kung cancer A549 cell resulted in increased NGF-stimulated invasive activity, elevated adhesion to brain tissue slices and upregulation of integrin a3b1 expression. There were no differences between transfectant and parental cell line in other integrin expression levels. When inoculated intravenously to the tail vein in skid mice, transfectants induced numerous lung and brain metastases. On the other hand parental cells or mock transfectant induced plenty of lung metastases, but not brain metastasis. These results suggested ADAM9 might play a role in brain metastasis of lung cancer.Transfection of ADAM9 cDNA in fibrosarcoma HT1080 cell was preformed and FACS analysis of each integrin expression showed disappearance of only integrin a4 in transfectants while parental cell or mock transfectant expressed integrin a4. Decreased adhesion of transfectants to CS-1 peptide or VCAM-1 (vascular cell adhesion molecule-1), both of which are ligands of integrin a4b1, was observed. Migratory or invasive activity to CS-1 or VCAM-1 was also reduced. When inoculated intravenously to tail vein of nude mice, parent cells induced a number of lung metastases but marked decreased lung metastases were found in transfectants. There were no differences in the tumor after subcutaneous injection.These data suggested ADAM9 might play some roles in integrin expression and also in cancer metastasis.

ADAM是由金属蛋白酶和崩解素组成的膜结合分子。为了阐明ADAM在肺癌细胞EBC-1细胞中高脑转移亚线和骨转移亚线的表达，我们研究了ADAM分子在肺癌细胞转移中的作用。结果表明，adam9mrna在脑转移亚系中的表达水平明显高于骨转移亚系和亲本细胞系。转染ADAM9 cDNA于肝癌A549细胞，可增加ngf刺激的侵袭活性，增加对脑组织切片的粘附，上调整合素a3b1的表达。其他整合素的表达水平在转染细胞系和亲本细胞系之间没有差异。当将转染物静脉注射到滑鼠的尾静脉时，诱导了大量的肺和脑转移。另一方面，亲本细胞或模拟转染诱导大量肺转移，但没有脑转移。这些结果提示ADAM9可能在肺癌脑转移中起一定作用。将ADAM9 cDNA转染到纤维肉瘤HT1080细胞中，FACS分析各整合素表达的结果显示，只有整合素a4在转染物中消失，而亲本细胞或模拟转染物表达整合素a4。观察到，转染物对整合素a4b1配体CS-1肽或VCAM-1（血管细胞粘附分子-1）的粘附降低。对CS-1或VCAM-1的迁移或侵入活动也有所减少。将亲本细胞静脉注射到裸鼠尾静脉中，可诱导多种肺转移，但转染物的肺转移明显减少。皮下注射后两组肿瘤无明显差异。这些数据提示ADAM9可能在整合素表达和肿瘤转移中发挥一定作用。