Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Biochem Pharmacol. 2011 Jun 1;81(11):1286-95. doi: 10.1016/j.bcp.2011.03.016. Epub 2011 Mar 29.
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. WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins. However, the effect of WISP-1 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that WISP-1 increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells (JJ012 cells). We also found that human chondrosarcoma tissues had significant expression of the WISP-1 which was higher than that in normal cartilage. α5β1 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) inhibited the WISP-1-induced increase of the migration and MMP-2 up-regulation of chondrosarcoma cells. WISP-1 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, NF-κB inhibitors also suppressed the cell migration and MMP-2 expression enhanced by WISP-1. Moreover, WISP-1 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-2 promoter. Taken together, our results indicated that WISP-1 enhances the migration of chondrosarcoma cells by increasing MMP-2 expression through the α5β1 integrin receptor, FAK, MEK, ERK, p65 and NF-κB 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。软骨肉瘤易向肺部转移。WISP-1 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、Nov）家族。然而，WISP-1 对人软骨肉瘤细胞迁移活性的影响大多未知。在这里，我们发现 WISP-1 增加了人软骨肉瘤细胞（JJ012 细胞）的迁移和基质金属蛋白酶（MMP）-2 的表达。我们还发现，人软骨肉瘤组织中 WISP-1 的表达明显高于正常软骨。α5β1 单克隆抗体和 MAPK 激酶（MEK）抑制剂（PD98059 和 U0126）抑制了 WISP-1 诱导的软骨肉瘤细胞迁移增加和 MMP-2 上调。WISP-1 刺激增加了粘着斑激酶（FAK）、MEK 和细胞外信号调节激酶（ERK）的磷酸化。此外，NF-κB 抑制剂也抑制了 WISP-1 增强的细胞迁移和 MMP-2 表达。此外，WISP-1 增加了 NF-κB 荧光素酶活性和 p65 与 MMP-2 启动子上 NF-κB 元件的结合。总之，我们的结果表明，WISP-1 通过增加 MMP-2 的表达，通过 α5β1 整合素受体、FAK、MEK、ERK、p65 和 NF-κB 信号转导通路增强软骨肉瘤细胞的迁移。
