Gondi Christopher S, Lakka Sajani S, Dinh Dzung H, Olivero William C, Gujrati Meena, Rao Jasti S
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605, USA.
Clin Cancer Res. 2007 Jul 15;13(14):4051-60. doi: 10.1158/1078-0432.CCR-06-3032.
The purpose of this study was to evaluate the therapeutic potential of using plasmid-expressed RNA interference (RNAi) targeting urokinase-type plasminogen activator (uPA) receptor (uPAR) and uPA to treat human glioma.
In the present study, we have used plasmid-based RNAi to simultaneously down-regulate the expression of uPAR and uPA in SNB19 glioma cell lines and epidermal growth factor receptor (EGFR)--overexpressing 4910 human glioma xenografts in vitro and in vivo, and evaluate the i.p. route for RNAi-expressing plasmid administered to target intracranial glioma.
Plasmid-mediated RNAi targeting uPAR and uPA did not induce OAS1 expression as seen from reverse transcription-PCR analysis. In 4910 EGFR-overexpressing cells, down-regulation of uPAR and uPA induced the down-regulation of EGFR and vascular endothelial growth factor and inhibited angiogenesis in both in vitro and in vivo angiogenic assays. In addition, invasion and migration were inhibited as indicated by in vitro spheroid cell migration, Matrigel invasion, and spheroid invasion assays. We did not observe OAS1 expression in mice with preestablished intracranial tumors, which were given i.p. injections of plasmid-expressing small interfering RNA--targeting uPAR and uPA. Furthermore, the small interfering RNA plasmid targeting uPAR and uPA caused regression of preestablished intracranial tumors when compared with the control mice.
In conclusion, the plasmid-expressed RNAi targeting uPAR and uPA via the i.p. route has potential clinical applications for the treatment of glioma.
本研究旨在评估使用质粒表达的RNA干扰（RNAi）靶向尿激酶型纤溶酶原激活剂（uPA）受体（uPAR）和uPA治疗人类胶质瘤的治疗潜力。
在本研究中，我们使用基于质粒的RNAi在体外和体内同时下调SNB19胶质瘤细胞系以及表皮生长因子受体（EGFR）过表达的4910人胶质瘤异种移植模型中uPAR和uPA的表达，并评估将表达RNAi的质粒经腹腔注射给药以靶向颅内胶质瘤的途径。
逆转录 - PCR分析显示，靶向uPAR和uPA的质粒介导的RNAi未诱导OAS1表达。在4910 EGFR过表达细胞中，uPAR和uPA的下调诱导了EGFR和血管内皮生长因子的下调，并在体外和体内血管生成试验中抑制了血管生成。此外，体外球体细胞迁移、基质胶侵袭和球体侵袭试验表明侵袭和迁移受到抑制。在预先建立颅内肿瘤并经腹腔注射靶向uPAR和uPA的表达小干扰RNA的质粒的小鼠中，我们未观察到OAS1表达。此外，与对照小鼠相比，靶向uPAR和uPA的小干扰RNA质粒导致预先建立的颅内肿瘤消退。
总之，通过腹腔途径靶向uPAR和uPA的质粒表达RNAi在治疗胶质瘤方面具有潜在的临床应用价值。
