Mohanam Sanjeeva, Chandrasekar Nirmala, Yanamandra Niranjan, Khawar Siddique, Mirza Faiz, Dinh Dzung H, Olivero William C, Rao Jasti S
Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61656-1649, USA.
Oncogene. 2002 Nov 7;21(51):7824-30. doi: 10.1038/sj.onc.1205893.
The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on the surface of tumor cells is involved in the activation of proteolytic cascades responsible for the invasiveness of those cells. The diffuse, extensive infiltration of glioblastomas into the surrounding normal brain tissue is believed to rely on modifications of the proteolysis of extracellular matrix components; blocking the interaction between uPA and uPAR might be a suitable approach for inhibiting glioma tumorigenesis. We assessed how expression of an amino-terminal fragment (ATF) of uPA that contains binding site to uPAR affects the invasiveness of SNB19 human glioblastoma cells. SNB19 cells were transfected with an expression plasmid (pcDNA3-ATF) containing a cDNA sequence of ATF-uPA. The resulting ATF-uPA-expressing clones showed markedly less cell adhesion, spreading, and clonogenicity than did control cells. Endogenous ATF expression also significantly decreased the invasive capacity of transfected glioblastoma cells in Matrigel and spheroid-rat brain cell aggregate models. ATF-uPA transfectants were also markedly less invasive than parental SNB19 cells after injection into the brains of nude mice, suggesting that competitive inhibition of the uPA-uPAR interaction on SNB19 cells by means of transfection with ATF cDNA could be a useful therapeutic strategy for inhibiting tumor progression.
尿激酶型纤溶酶原激活剂（uPA）与其在肿瘤细胞表面的受体（uPAR）结合，参与了导致这些细胞侵袭性的蛋白水解级联反应的激活。胶质母细胞瘤向周围正常脑组织的弥漫性、广泛浸润被认为依赖于细胞外基质成分蛋白水解的改变；阻断uPA与uPAR之间的相互作用可能是抑制胶质瘤肿瘤发生的一种合适方法。我们评估了含有uPAR结合位点的uPA氨基末端片段（ATF）的表达如何影响SNB19人胶质母细胞瘤细胞的侵袭性。用含有ATF - uPA cDNA序列的表达质粒（pcDNA3 - ATF）转染SNB19细胞。与对照细胞相比，所得表达ATF - uPA的克隆显示出明显较少的细胞黏附、铺展和克隆形成能力。在基质胶和球状体 - 大鼠脑细胞聚集体模型中，内源性ATF表达也显著降低了转染的胶质母细胞瘤细胞的侵袭能力。将ATF - uPA转染细胞注射到裸鼠脑内后，其侵袭性也明显低于亲代SNB19细胞，这表明通过用ATF cDNA转染对SNB19细胞上的uPA - uPAR相互作用进行竞争性抑制可能是抑制肿瘤进展的一种有用治疗策略。
