Expression of antisense uPAR and antisense uPA from a bicistronic adenoviral construct inhibits glioma cell invasion, tumor growth, and angiogenesis
Expression of antisense uPAR and antisense uPA from a bicistronic adenoviral construct inhibits glioma cell invasion, tumor growth, and angiogenesis
复制标题
DOI：
10.1038/sj.onc.1206535
复制
发表时间：
2003-09-04
期刊：
影响因子：
8
通讯作者：
Rao, JS
中科院分区：
文献类型：
--
作者：
Gondi, CS;Lakka, SS;Rao, JS
尿激酶型纤溶酶原激活物（uPA）及其受体（uPAR）在胶质瘤等浸润性肿瘤的侵袭性中起重要作用。在神经胶质瘤细胞系和肿瘤中，高级别与uPAR和uPA表达增加相关。我们在这里报告的下调uPAR和uPA通过交付的反义序列的uPAR和uPA在一个单一的腺病毒载体，Ad-uPAR-uPA（Ad，腺病毒）。与对照组相比，双顺反子构建体（Ad-uPAR-uPA）感染的胶质母细胞瘤细胞系的uPAR、uPA酶活性和这些蛋白的免疫反应性水平显著降低。Ad-uPAR-uPA感染的细胞在Matrigel侵袭实验中表现出明显较低的侵袭水平，并且它们的球状体在共培养系统中不能侵袭胎鼠脑聚集体。颅内注射Ad-uPAR-uPA反义双顺反子构建体的SNB 19细胞显示抑制侵袭性和致瘤性。将双顺反子反义构建体皮下注射到已建立的肿瘤（U87 MG）中引起这些肿瘤的消退。我们的结果支持通过使用单个腺病毒构建体靶向uPAR-uPA系统的各个组分用于治疗神经胶质瘤和其他侵袭性癌症的治疗潜力。
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the invasiveness of gliomas and other infiltrative tumors. In glioma cell lines and tumors, high grade correlates with increased expression of uPAR and uPA. We report here the downregulation of uPAR and uPA by delivery of antisense sequences of uPAR and uPA in a single adenoviral vector, Ad-uPAR-uPA (Ad, adenovirus). The bicistronic construct (Ad-uPAR-uPA) infected glioblastoma cell line had significantly reduced levels of uPAR, uPA enzymatic activity and immunoreactivity for these proteins when compared to controls. The Ad-uPAR-uPA infected cells showed a markedly lower level of invasion in the Matrigel invasion assays, and their spheroids failed to invade the fetal rat brain aggregates in the coculture system. Intracranial injection of SNB19 cells with the Ad-uPAR-uPA antisense bicistronic construct showed inhibited invasiveness and tumorigenicity. Subcutaneous injections of bicistronic antisense constructs into established tumors (U87 MG) caused regression of those tumors. Our results support the therapeutic potential of targeting the individual components of the uPAR-uPA system by using a single adenovirus construct for the treatment of glioma and other invasive cancers.