Endothelial CD146 is required for in vitro tumor-induced angiogenesis: The role of a disulfide bond in signaling and dimerization
Endothelial CD146 is required for in vitro tumor-induced angiogenesis: The role of a disulfide bond in signaling and dimerization
复制标题
DOI：
10.1016/j.biocel.2009.03.014
复制
发表时间：
2009-11-01
影响因子：
4
通讯作者：
Yan, Xiyun
中科院分区：
文献类型：
--
作者：
Zheng, Chaogu;Qiu, Yijun;Yan, Xiyun
由肿瘤分泌的促血管生成因子诱导的肿瘤血管生成是癌症发展和转移的重要过程，CD 146被鉴定为内皮细胞粘附分子并参与血管形成。然而，它在血管生成中的确切作用。特别是肿瘤血管生成，其潜在的功能，介导下游信号仍然是不清楚的。在本研究中，我们证明，通过RNAi沉默内源性内皮CD 146显着损害肝癌细胞的分泌，促进管状形态发生和增强内皮细胞的运动。生化研究表明，CD 146是激活p38/IKK/NF κ B B信号级联和上调NF κ B B下游促血管生成基因所必需的。特别是IL-8、ICAM-1和MMP 9，以响应肿瘤分泌物。有趣的是，特异性抗CD 146 mAb AA 98结合依赖于C452-C499二硫键的构象表位，可以消除NF κ B B活化和肿瘤血管生成，而另一种识别含有aa 50 -54的线性表位的抗CD 146 mAb AA 1没有这样的作用。进一步的结构-功能分析表明，第五胞外IG结构域中的C452-C499二硫键对于CD 146介导的信号传导和管形成是不可缺少的。此外，CD 146的二聚化被肿瘤分泌物增强，AA 98而不是AA 1抑制。也依赖于C452和C499。总之，这项研究首次揭示了CD 146的促血管生成作用，并确定了负责其信号功能和二聚化的关键结构基础。这些发现还表明，CD 146可能不仅是一种细胞粘附分子，也是肿瘤诱导血管生成中的膜信号受体（C）2009 Elsevier Ltd.保留所有权利。
Tumor angiogenesis, induced by tumor-secreted pro-angiogenic factors, is an essential process for cancer development and metastasis CD146 is identified as an endothelial cell adhesion molecule and implicated in blood vessel formation. however, its exact role in angiogenesis. particularly tumor angiogenesis, and its potential function of mediating downstream signaling are still unclear In present study, we evidenced that silencing endogenous endothelial CD146 by RNAi significantly impaired hepatocarcinoma cell secretions-promoted tubular morphogenesis and -enhanced motility of endothelial cells. Biochemical studies revealed that CD146 was required for the activation of p38/IKK/NF kappa B signaling cascade and up-regulation of NF kappa B downstream pro-angiogenic genes. notably IL-8, ICAM-1 and MMP9, in response to tumor secretions. Interestingly, specific anti-CD146 mAb AA98, which bound a conformational epitope depending on C452-C499 disulfide bond, could abrogate NF kappa B activation and tumor angiogenesis, whereas another anti-CD146 mAb AA1 recognizing a linear epitope containing aa50-54 did not have such effects. Further structure-function analysis identified that C452-C499 disulfide bond within the fifth extracellular Ig domain was indispensible for CD146-mediated signaling and tube formation Moreover, dimerization of CD146, which was enhanced by tumor secretions and suppressed by AA98 but not AA1. also relied on C452 and C499. Together, this study for the first time uncovered the pro-angiogenic role of CD146 and also pinpointed the key structural basis responsible for its signaling function and dimerization. These findings also suggested that CD146 might serve as not just a cell adhesion molecule but also a membrane signal receptor in tumor-induced angiogenesis (C) 2009 Elsevier Ltd. All rights reserved.