School of Chinese Medicine, China Medical University, Taichung, Taiwan.
J Cell Physiol. 2012 Jan;227(1):223-32. doi: 10.1002/jcp.22720.
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN6 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, and Nov) family of matricellular proteins. However, the effects of CCN6 on human chondrosarcoma cells are largely unknown. In this study, we found that CCN6 increased the migration and the expression of intercellular adhesion molecule-1 (ICAM-1) in human chondrosarcoma cells. αvβ3 and αvβ5 integrin monoclonal antibody and mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) inhibited the CCN6-induced increase of the migration and ICAM-1 up-regulation of chondrosarcoma cells. CCN6 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK, and extracellular signal-regulated kinase (ERK). In addition, activator protein-1 (AP-1) inhibitors suppressed the cell migration and ICAM-1 expression enhanced by CCN6. Moreover, CCN6 increased AP-1 luciferase activity and binding of c-Jun to the AP-1 element on the ICAM-1 promoter. Taken together, our results indicate that CCN6 enhances the migration of chondrosarcoma cells by increasing ICAM-1 expression through the αvβ3 and αvβ5 integrin receptor, FAK, MEK, ERK, c-Jun, and AP-1 signal transduction pathway.
软骨肉瘤是一种高度恶性肿瘤，具有很强的局部侵袭和远处转移能力。软骨肉瘤表现出向肺部转移的倾向。CCN6 是一种富含半胱氨酸的蛋白质，属于细胞基质蛋白的 CCN（Cyr61、CTGF 和 Nov）家族。然而，CCN6 对人软骨肉瘤细胞的影响在很大程度上尚不清楚。在这项研究中，我们发现 CCN6 增加了人软骨肉瘤细胞的迁移和细胞间黏附分子-1（ICAM-1）的表达。αvβ3 和 αvβ5 整合素单克隆抗体和丝裂原活化蛋白激酶（MEK）抑制剂（PD98059 和 U0126）抑制了 CCN6 诱导的人软骨肉瘤细胞迁移增加和 ICAM-1 上调。CCN6 刺激增加了黏着斑激酶（FAK）、MEK 和细胞外信号调节激酶（ERK）的磷酸化。此外，激活蛋白-1（AP-1）抑制剂抑制了 CCN6 增强的细胞迁移和 ICAM-1 表达。此外，CCN6 增加了 AP-1 荧光素酶活性和 c-Jun 与 ICAM-1 启动子上的 AP-1 元件的结合。总之，我们的结果表明，CCN6 通过增加 αvβ3 和 αvβ5 整合素受体、FAK、MEK、ERK、c-Jun 和 AP-1 信号转导通路，增加 ICAM-1 的表达，增强软骨肉瘤细胞的迁移。
