Hu Bo, Jarzynka Michael J, Guo Ping, Imanishi Yorihisha, Schlaepfer David D, Cheng Shi-Yuan
University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Cancer Res. 2006 Jan 15;66(2):775-83. doi: 10.1158/0008-5472.CAN-05-1149.
Accumulating evidence reveals a significant correlation between angiopoietin 2 (Ang2) expression and tumor invasion and metastasis in various human cancers, but the major focus of recent studies has been on the angiogenic effects of Ang2. We recently reported that Ang2-stimulated glioma cell invasion results from the up-regulation and activation of matrix metalloprotease 2 (MMP-2) in tumor cells. In this study, we identify a novel mechanism by which Ang2 stimulates MMP-2 expression leading to glioma cell invasion. We show that Ang2 interacts with alpha(v)beta(1) integrin in Tie2-deficient human glioma cells, activating focal adhesion kinase (FAK), p130(Cas), extracellular signal-regulated protein kinase (ERK) 1/2, and c-jun NH(2)-terminal kinase (JNK) and substantially enhancing MMP-2 expression and secretion. The Ang2/alpha(v)beta(1) integrin signaling pathway was attenuated by functional inhibition of beta(1) and alpha(v) integrins, FAK, p130(Cas), ERK1/2, and JNK. Furthermore, expression of a negative regulator of FAK, FAK-related nonkinase, by U87MG/Ang2-expressing glioma xenografts suppressed Ang2-induced MMP-2 expression and glioma cell infiltration in the murine brain. These data establish a functional link between Ang2 interaction with alpha(v)beta(1) integrin and glioma cell invasion through the FAK/p130(Cas)/ERK1/2 and JNK-mediated signaling pathway.
越来越多的证据表明，血管生成素2（Ang2）的表达与多种人类癌症中的肿瘤侵袭和转移之间存在显著相关性，但最近的研究主要集中在Ang2的血管生成作用上。我们最近报道，Ang2刺激的胶质瘤细胞侵袭是由肿瘤细胞中基质金属蛋白酶2（MMP-2）的上调和激活引起的。在本研究中，我们确定了一种新的机制，通过该机制Ang2刺激MMP-2表达导致胶质瘤细胞侵袭。我们发现，在缺乏Tie2的人胶质瘤细胞中，Ang2与α（v）β（1）整合素相互作用，激活粘着斑激酶（FAK）、p130（Cas）、细胞外信号调节蛋白激酶（ERK）1/2和c-jun氨基末端激酶（JNK），并显著增强MMP-2的表达和分泌。β（1）和α（v）整合素、FAK、p130（Cas）、ERK1/2和JNK的功能抑制减弱了Ang2/α（v）β（1）整合素信号通路。此外，表达FAK负调节因子FAK相关非激酶的U87MG/Ang2表达的胶质瘤异种移植瘤抑制了Ang2诱导的MMP-2表达和胶质瘤细胞在小鼠脑中的浸润。这些数据建立了Ang2与α（v）β（1）整合素相互作用与通过FAK/p130（Cas）/ERK1/2和JNK介导的信号通路导致的胶质瘤细胞侵袭之间的功能联系。
