Tan Tzu-Wei, Lai Chih-Ho, Huang Chun-Yiu, Yang Wei-Hung, Chen Hsien-Te, Hsu Horng-Chaung, Fong Yi-Chin, Tang Chih-Hsin
Department of Pharmacology, China Medical University, Taichung, Taiwan.
J Cell Biochem. 2009 May 15;107(2):345-56. doi: 10.1002/jcb.22132.
Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CTGF on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CTGF increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). RGD peptide, alphavbeta3 monoclonal antibody (mAb) and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the CTGF-induced increase of the migration and MMP-13 up-regulation of chondrosarcoma cells. CTGF stimulation increased the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In addition, treatment of JJ012 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited CTGF-induced cell migration and MMP-13 up-regulation. Stimulation of JJ012 cells with CTGF also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The CTGF-mediated increases in kappaB-luciferase activities were inhibited by RGD, PD98059, U0126 or FAK, and ERK2 mutant. Taken together, our results indicated that CTGF enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the alphavbeta3 integrin, FAK, ERK, and NF-kappaB signal transduction pathway.
肿瘤恶性程度与多种特征相关，如增殖能力和转移频率。结缔组织生长因子（CTGF）是一种与整合素结合的分泌蛋白，可调节某些人类癌细胞的侵袭行为。然而，CTGF对人软骨肉瘤细胞迁移活性的影响大多未知。在此我们发现，CTGF可增加人软骨肉瘤细胞（JJ012细胞）中基质金属蛋白酶（MMP）-13的迁移和表达。RGD肽、αvβ3单克隆抗体（mAb）和丝裂原活化蛋白激酶（MEK）抑制剂（PD98059和U0126）而非RAD肽可抑制CTGF诱导的软骨肉瘤细胞迁移增加和MMP-13上调。CTGF刺激可增加粘着斑激酶（FAK）和细胞外信号调节激酶（ERK）的磷酸化。此外，用核因子κB抑制剂（PDTC）或IκB蛋白酶抑制剂（TPCK）处理JJ012细胞可抑制CTGF诱导的细胞迁移和MMP-13上调。用CTGF刺激JJ012细胞还可诱导IκB激酶α/β（IKKα/β）磷酸化、IκBα磷酸化、p65 Ser(536)磷酸化以及κB-荧光素酶活性。RGD、PD9八百零59、U0126或FAK和ERK2突变体可抑制CTGF介导的κB-荧光素酶活性增加。综上所述，我们的结果表明，CTGF通过αvβ3整合素、FAK、ERK和核因子κB信号转导途径增加MMP-13表达，从而增强软骨肉瘤细胞的迁移。
