A chimeric antibody targeting CD147 inhibits hepatocellular carcinoma cell motility via FAK-PI3K-Akt-Girdin signaling pathway
A chimeric antibody targeting CD147 inhibits hepatocellular carcinoma cell motility via FAK-PI3K-Akt-Girdin signaling pathway
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DOI：
10.1007/s10585-014-9689-7
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发表时间：
2014-11
影响因子：
4
通讯作者：
Yuan Wang;Lin Yuan;Xiang-min Yang;D. Wei;Bin Wang;Xiu-Xuan Sun;Fei Feng;Gang Nan;Ye Wang
中科院分区：
文献类型：
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作者：
Yuan Wang;Lin Yuan;Xiang-min Yang;D. Wei;Bin Wang;Xiu-Xuan Sun;Fei Feng;Gang Nan;Ye Wang
CD147在正常组织中表达水平较低，但在肺、乳腺和肝脏等多种肿瘤类型中经常高表达，因此它是这些不同肿瘤类型的潜在独特治疗靶点。我们之前制备了一种小鼠抗体HAb18，它可以抑制基质金属蛋白酶-2和基质金属蛋白酶-9的分泌，通过阻断肿瘤细胞中的CD147分子来减弱细胞侵袭。在这里，我们生成了一种嵌合抗体，包含小鼠HAb18的可变重链和可变轻链以及人类IgG1γ1和人类κ链的恒定区域，作为潜在的治疗剂（命名为cHAb18）。用表面等离子体共振定量测定cHAb18抗体对抗原CD147的亲和力，结果表明其平衡解离常数kd2.66 × 10−10mol/L，与小鼠HAb18的平衡解离常数KD2.73 × 10−10mol/L相似。cHAb18在两种肝癌细胞系SMMC-7721和Huh-7细胞中诱导抗体依赖细胞介导的细胞毒性。它通过特异性阻断CD147抑制肝癌细胞的侵袭和迁移。除了抑制基质金属蛋白酶-2和基质金属蛋白酶-9的表达外，cHAb18抗体还通过肌动蛋白骨架的重排抑制细胞运动，这可能是通过降低整合素信号通路中局点黏着激酶、磷脂酰亚苷-3激酶（PI3K）、Akt和Girdin的磷酸化诱导的。在BALB/c裸鼠原位肝癌模型中，cHAb18治疗可有效减少肝脏肿瘤转移，延长生存期。这些发现揭示了靶向CD147的cHAb18抗体在肿瘤治疗中的新的治疗潜力。
CD147 is expressed at low levels in normal tissues but frequently highly expressed in a wide range of tumor types such as lung, breast, and liver and therefore it is a potentially unique therapeutic target for these diverse tumor types. We previously generated a murine antibody HAb18 which suppresses matrix met al.loproteinase-2 and matrix metalloproteinase-9 secretion, attenuates cell invasion by blocking the CD147 molecule in tumor cells. Here, we generated a chimeric antibody containing the variable heavy and variable light chains of murine HAb18 and the constant regions of human IgG1γ1 and human κ chain as a potential therapeutic agent (designated cHAb18). Quantitative measurement of cHAb18 antibody affinity for antigen CD147 with surface plasmon resonance showed the equilibrium dissociation constant KDwas 2.66 × 10−10mol/L, similar to that of KD2.73 × 10−10mol/L for murine HAb18. cHAb18 induced antibody-dependent cell-mediated cytotoxicity in two hepatocellular carcinoma cell lines, SMMC-7721 and Huh-7 cells. It inhibited cancer invasion and migration in hepatocellular carcinoma cells by specifically blocking CD147. Except for the depression of matrix metalloproteinase-2 and matrix metalloproteinase-9 expressions, cHAb18 antibody suppressed cell motility by rearrangement of actin cytoskeleton, which was probably induced by decreasing the phosphorylation of focal adhesion kinase, phosphatidylinositide-3 kinase (PI3K), Akt, and Girdin in the integrin signaling pathway. In an orthotopic model of hepatocellular carcinoma in BALB/c nude mice, cHAb18 treatment effectively reduced the tumor metastasis in liver and prolonged the survival. These findings reveal new therapeutic potential for cHAb18 antibody targeting CD147 on tumor therapy.