Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(2):258-268; doi:10.1093/carcin/bgn284
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Cyr61 increases migration and MMP-13 expression via 
vβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells
1 Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan
2 Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan
3 Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 402, Taiwan
4 Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County 651, Taiwan
5 School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
6 Department of Nursing and Management, Jen-Teh Junior College of Medicine, Miaoli County 305, Taiwan
7 Graduate Institute of Acupuncture Science
8 Graduate Institute of Chinese Medical Science
9 Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan
10 Department of Orthopaedics, China Medical University Hospital, Taichung 404, Taiwan
* To whom correspondence should be addressed. Tel: +886 4 22053366 ext. 2228; Fax: +886 4 22053764; Email: chtang{at}mail.cmu.edu.tw
Correspondence may also be addressed to Yi-Chin Fong. Tel: +886 4 22062121 ext. 2073; Fax: +886 4 22038316; Email: yichin.fong{at}mail.cmu.edu.tw
Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secreted and matrix-associated protein, which is involved in many cellular activities such as growth and differentiation. However, the effect of Cyr61 on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that Cyr61 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). RGD peptide, 
vβ3 monoclonal antibody and mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the Cyr61-induced increase of the migration and MMP-13 upregulation of chondrosarcoma cells. Cyr61 stimulation increased the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In addition, activator protein-1 (AP-1) decoy oligodeoxynucleotide also suppressed the MMP-13 messenger RNA and enzyme activity enhanced by Cyr61. Moreover, Cyr61 increased the binding of c-Fos and c-Jun to the AP-1 element on the MMP-13 promoter. Taken together, our results indicated that Cyr61 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the vβ3 integrin receptor, FAK, ERK, c-Fos/c-Jun and AP-1 signal transduction pathway.
Abbreviations: AP-1, activator protein-1; AS, antisense; Cyr61, cysteine-rich 61; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; mAb, monoclonal antibody; MEK, MAPK kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; MS, missense; NF-
B, nuclear factor-kappa B; ODN, oligonucleotide; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; qPCR, quantitative real-time polymerase chain reaction; siRNA, small-interfering RNA
These authors contributed equally to this work. Received July 22, 2008; revised November 5, 2008; accepted December 9, 2008.