Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan.
J Cell Physiol. 2011 Dec;226(12):3181-9. doi: 10.1002/jcp.22672.
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. CCN3, also called nephroblastoma overexpressed gene (NOV), regulates proliferation and differentiation of cancer cells. However, the effect of CCN3 on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that CCN3 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). αvβ3 or αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase (PI3K) inhibitors (Ly294002 and wortmannin) and Akt inhibitor inhibited the CCN3-induced increase of the migration and MMP-13 upregulation of chondrosarcoma cells. CCN3 stimulation increased the phosphorylation of focal adhesion kinase (FAK), PI3K, and Akt. In addition, NF-κB inhibitors also suppressed the cell migration and MMP-13 expression enhanced by CCN3. Moreover, CCN3 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-13 promoter. Taken together, our results indicate that CCN3 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the αvβ3/αvβ5 integrin receptor, FAK, PI3K, Akt, p65, and NF-κB signal transduction pathway.
软骨肉瘤是一种高度恶性的肿瘤，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。卷曲相关蛋白 3（CCN3），也称为肾母细胞瘤过表达基因（NOV），调节癌细胞的增殖和分化。然而，CCN3 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 CCN3 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）-13 的表达。αvβ3 或 αvβ5 单克隆抗体（mAb）、磷脂酰肌醇 3-激酶（PI3K）抑制剂（Ly294002 和 wortmannin）和 Akt 抑制剂抑制了 CCN3 诱导的软骨肉瘤细胞迁移增加和 MMP-13 的上调。CCN3 刺激增加了黏着斑激酶（FAK）、PI3K 和 Akt 的磷酸化。此外，NF-κB 抑制剂也抑制了 CCN3 增强的细胞迁移和 MMP-13 表达。此外，CCN3 增加了 NF-κB 荧光素酶活性和 p65 与 MMP-13 启动子上 NF-κB 元件的结合。总之，我们的结果表明，CCN3 通过增加 MMP-13 的表达增强软骨肉瘤细胞的迁移，通过 αvβ3/αvβ5 整联蛋白受体、FAK、PI3K、Akt、p65 和 NF-κB 信号转导通路。
