Knockdown of cathepsin B and uPAR inhibits CD151 and α3β1 integrin-mediated cell adhesion and invasion in glioma.
Knockdown of cathepsin B and uPAR inhibits CD151 and α3β1 integrin-mediated cell adhesion and invasion in glioma.
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DOI：
10.1002/mc.21915
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发表时间：
2013-10
影响因子：
4.6
通讯作者：
Rao, Jasti S.
中科院分区：
文献类型：
--
作者：
Malla, Rama Rao;Gopinath, Sreelatha;Alapati, Kiranmai;Gorantla, Bharathi;Gondi, Christopher S.;Rao, Jasti S.
胶质瘤是一种高度复杂的脑肿瘤，其特征是蛋白质和基因的失调，导致肿瘤转移。组织蛋白酶B和uPAR在胶质瘤中过度表达，它们被认为在胶质瘤转移中起核心作用。在这项研究中，在U251和4910胶质瘤细胞系中，与玻璃体连接蛋白、纤维连接蛋白或I型胶原相比，siRNA处理有效下调组织蛋白酶B和uPAR可显著降低胶质瘤细胞对层粘连蛋白的粘附。脑胶质瘤组织阵列分析显示，与正常脑组织相比，临床样本中CD151的表达较高。组织蛋白酶B和uPAR siRNA处理导致CD151和层粘连蛋白结合整合素α3和β1的下调。共免疫沉淀实验显示，下调组织蛋白酶B和uPAR可降低CD151与uPAR和α3β1整合素的相互作用。对uPAR/CD151/α3β1整合素下游信号级联的研究表明，FAK、SRC、paxillin的磷酸化以及接头细胞骨架蛋白talin和vinculin的表达随着组织蛋白酶B、uPAR和CD151的下调而降低。在裸鼠神经胶质瘤中，双链结构降低了uPAR和CD151之间的相互作用，并降低了α3β1整合素、talin和vinculin的表达水平。综上所述，我们的研究结果表明，在体外和体内，组织蛋白酶B和uPAR单独或联合下调通过下调CD151及其相关信号分子抑制胶质瘤细胞粘附。综上所述，本研究的结果表明，靶向upar -组织蛋白酶B系统具有可能的治疗潜力。
Glioma is a highly complex brain tumor characterized by the dysregulation of proteins and genes that leads to tumor metastasis. Cathepsin B and uPAR are overexpressed in gliomas and they are postulated to play central roles in glioma metastasis. In this study, efficient downregulation of cathepsin B and uPAR by siRNA treatments significantly reduced glioma cell adhesion to laminin as compared to vitronectin, fibronectin, or collagen I in U251 and 4910 glioma cell lines. Brain glioma tissue array analysis showed high expression of CD151 in clinical samples when compared with normal brain tissue. Cathepsin B and uPAR siRNA treatment led to the downregulation of CD151 and laminin-binding integrins α3 and β1. Co- immunoprecipitation experiments revealed that downregulation of cathepsin B and uPAR decreased the interaction of CD151 with uPAR and α3β1 integrin. Studies on the downstream signaling cascade of uPAR/CD151/α3β1 integrin have shown that phosphorylation of FAK, SRC, paxillin and expression of adaptor cytoskeletal proteins talin and vinculin were reduced with knockdown of cathepsin B, uPAR and CD151. Treatment with the bicistronic construct reduced interactions between uPAR and CD151 as well as lowering α3β1 integrin, talin, and vinculin expression levels in pre-established glioma tumors of nude mice. In conclusion, our results show that downregulation of cathepsin B and uPAR alone and in combination inhibit glioma cell adhesion by downregulating CD151 and its associated signaling molecules in vitro and in vivo. Taken together, the results of the present study show that targeting the uPAR-cathepsin B system has possible therapeutic potential.
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影响因子：
3.7
作者：
Malla R;Gopinath S;Alapati K;Gondi CS;Gujrati M;Dinh DH;Mohanam S;Rao JS
通讯作者：
Rao JS
影响因子：
6.4
作者：
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通讯作者：
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影响因子：
4.3
作者：
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通讯作者：
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影响因子：
8
作者：
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通讯作者：
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影响因子：
13.5
作者：
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通讯作者：
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