Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism
Endostar, a modified endostatin inhibits non small cell lung cancer cell in vitro invasion through osteopontin-related mechanism
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DOI：
10.1016/j.ejphar.2009.04.032
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发表时间：
2009-07-01
影响因子：
5
通讯作者：
Xu, Chengyun
中科院分区：
文献类型：
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作者：
Ni, Qinggui;Ji, Hui;Xu, Chengyun
本研究旨在探讨重组人内皮抑素（Endostar）及其修饰物对非小细胞肺癌（NSCLC）细胞侵袭的抑制作用及其可能的骨桥蛋白（OPN）机制。结果表明，恩度对高转移性NSCLC（NCI-H460）细胞的体外侵袭有明显的抑制作用。酶联免疫吸附试验表明，恩度降低骨桥蛋白水平可能是其抑制侵袭的机制之一。RT-PCR和western blot分析表明，骨桥蛋白的表达下调是由于骨桥蛋白表达下调所致。此外，Endostar还能抑制骨桥蛋白诱导的低转移性NSCLC（A549）细胞的侵袭，提示Endostar可能有其他不同的骨桥蛋白相关机制。在粘附试验中，我们发现Endostar减少了NCI-H460细胞与骨桥蛋白的结合。流式细胞术分析表明，粘附的减少可能与其受体（CD 44 v6和α（v）β（3）整合素）表达的调节不足有关。此外，我们发现，通过明胶酶谱分析，骨桥蛋白诱导的表达和激活的基质金属蛋白酶（MMP）-2和MMP-9前分泌的A549细胞被阻断后，恩度，表明恩度可能会阻止骨桥蛋白介导的信号转导途径通过MMIP家族。上述结果表明，Endostar可能通过骨桥蛋白相关机制对NSCLC具有内在的非血管生成相关的抗肿瘤活性，包括骨桥蛋白变化和骨桥蛋白信号转导阻断。肿瘤细胞的侵袭是肿瘤转移的重要因素，我们的研究结果提示，将恩度用于治疗NSCLC转移可能是一个很好的策略。(C)2009 Elsevier B. V.保留所有权利。
In this study, we studied the inhibition of non small cell lung cancer (NSCLC) cells invasion by a recombinant human Endostar, a modified endostatin and the possible osteopontin-related mechanism. The results showed that Endostar significantly inhibited highly metastatic NSCLC (NCI-H460) cells in vitro invasion. ELISA demonstrated that reduction of osteopontin level in the medium by Endostar may be responsible for the inhibition of invasion. RT-PCR assay and western blot analysis revealed that the reduction of osteopontin was due to under-regulation of osteopontin expression. Furthermore, Endostar also inhibited osteopontin-induced less metastatic NSCLC (A549) cells invasion, indicating that Endostar may have other different osteopontin-related mechanism. In an adhesion assay, we found that Endostar reduced NCI-H460 cells binding to osteopontin. Flow cytometric analysis suggested that the reduction of adhesion may be related to under-regulation of its receptors (CD44v6 and alpha(v)beta(3) integrin) expression. Additionally, we found, via gelatin zymographic analysis, that osteopontin-induced the expression and activation of pro-matrix metalloproteinase (MMP)-2 and pro MMP-9 secreted from A549 cells were blocked upon Endostar treatment, indicating that Endostar may block osteopontin-mediated signal transduction pathways through MMIP families. The above results indicate that Endostar may have an intrinsic non-angiogenesis-related antitumor activity through osteopontin-related mechanism against NSCLC, including osteopontin change and osteopontin signal transduction blockade. Tumor cell invasion is important for tumor metastasis, our findings suggest that it is probably a good strategy to put Endostar into treatment of NSCLC metastasis. (C) 2009 Elsevier B.V. All rights reserved.