Cathepsin B and uPAR knockdown inhibits tumor-induced angiogenesis by modulating VEGF expression in glioma.
Cathepsin B and uPAR knockdown inhibits tumor-induced angiogenesis by modulating VEGF expression in glioma.
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DOI：
10.1038/cgt.2011.9
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发表时间：
2011-06
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
血管生成是新血管从预先存在的血管发芽的过程，对于肿瘤进展至关重要。细胞外基质的蛋白水解重构是血管新生过程中血管出芽的关键事件。已知尿激酶纤溶酶原激活物受体（uPAR）和组织蛋白酶B均过表达并与肿瘤血管生成有关。在本研究中，我们观察到使用puPAR（pU）、pCathepsin B（pC）以及uPAR和组织蛋白酶B（pCU）的双顺反子构建体敲低uPAR和组织蛋白酶B通过破坏VEGF的JAK/STAT途径依赖性表达而引起血管生成的显著抑制。此外，uPAR和组织蛋白酶B的转录抑制抑制肿瘤诱导的迁移和内皮细胞的增殖，并降低肿瘤促进的VEGFR-2，Rac 1，gp 91 phox，细胞周期蛋白D1，Cdk 4和p-Rb在HMEC中的表达。此外，来自用pCU处理的裸鼠的U251和SNB 19异种移植物组织切片显示VEGF和CD 31（其是血管可视化标志物）的表达降低。总之，结果显示，敲低uPAR和组织蛋白酶B通过破坏JAK/STAT途径依赖的VEGF表达来抑制肿瘤诱导的血管生成。这些数据提供了新的见解，在表征参与血管生成级联反应的途径，并确定新的靶蛋白用于神经胶质瘤的治疗干预。
Angiogenesis, which is the process of sprouting of new blood vessels from pre-existing vessels, is vital for tumor progression. Proteolytic remodeling of extracellular matrix is a key event in vessel sprouting during angiogenesis. Urokinase plasminogen activator receptor (uPAR) and cathepsin B are both known to be overexpressed and implicated in tumor angiogenesis. In the present study, we observed that knockdown of uPAR and cathepsin B using puPAR (pU), pCathepsin B (pC), and a bicistronic construct of uPAR and cathepsin B (pCU) caused significant inhibition of angiogenesis by disrupting the JAK/STAT pathway-dependent expression of VEGF. Further, transcriptional suppression of uPAR and cathepsin B inhibited tumor-induced migration, and proliferation of endothelial cells and decreased tumor-promoted expression of VEGFR-2, Rac1, gp91phox, cyclin D1, Cdk4, and p-Rb in HMEC. Furthermore, U251 and SNB19 xenograft tissue sections from nude mice treated with pCU showed reduced expression of VEGF and CD31, which is a blood vessel visualization marker. Overall, results revealed that knockdown of uPAR and cathepsin B inhibited tumor-induced angiogenesis by disrupting the JAK/STAT pathway-dependent expression of VEGF. These data provide new insight in characterizing the pathways involved in the angiogenic cascade and for the identification of novel target proteins for use in therapeutic intervention for gliomas.
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影响因子：
5.3
作者：
Havens, Courtney G.;Ho, Alan;Dowdy, Steven F.
通讯作者：
Dowdy, Steven F.
影响因子：
5.7
作者：
Gondi, Christopher S.;Kandhukuri, Neelima;Rao, Jasti S.
通讯作者：
Rao, Jasti S.
影响因子：
4.1
作者：
BUCK, MR;KARUSTIS, DG;SLOANE, BF
通讯作者：
SLOANE, BF
DOI：
10.1084/jem.181.4.1381
发表时间：
1995-04-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bohuslav J;Horejsí V;Hansmann C;Stöckl J;Weidle UH;Majdic O;Bartke I;Knapp W;Stockinger H
通讯作者：
Stockinger H
影响因子：
8
作者：
Gondi, CS;Lakka, SS;Rao, JS
通讯作者：
Rao, JS