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Carcinogenesis Advance Access published online on January 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgn284
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cyr61 increases migration and MMP-13 expression via {alpha}vβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells

Tzu-Wei Tan1,9, Wei-Hung Yang7,10,5, Yuh-Tzy Lin8, Sheng-Feng Hsu2, Te-Mao Li2, Shung-Te Kao6, Wen-Chi Chen3, Yi-Chin Fong4,5,6,* and Chih-Hsin Tang1,9,*

1 Department of Pharmacology, China Medical University, Taichung, Taiwan
2 Graduate Institute of Acupuncture Science
3 Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
4 Department of Orthopaedic, China Medical University Hospital, Taichung, Taiwan
5 School of Chinese Medicine
6 Graduate Institute of Chinese Medical Science
9 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
8 Department of Nursing and Management, Jen-Teh Junior College of Medicine, Miaoli County, Taiwan
7 Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
10 Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan

* Author for Correspondence: Tang Chih-Hsin, Department of Pharmacology, College of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung, Taiwan, Tel: (886) 4-22053366 Ext. 2228. Fax: (886) 4-22053764. E-mail: chtang{at}mail.cmu.edu.tw Or Fong, Yi-Chin; Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan. E-mail: yichin.fong{at}mail.cmu.edu.tw, T.-W. Tan and W.-H. Yang contributed equally to this study.

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, {alpha}vβ3 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the Cyr61-induced increase of the migration and MMP-13 up-regulation of chondrosarcoma cells. Cyr61 stimulation increased the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In addition, AP-1 decoy oligodeoxynucleotide also suppressed the MMP-13 mRNA 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 {alpha}vβ3 integrin receptor, FAK, ERK, c-Fos/c-Jun and AP-1 signal transduction pathway.

Key Words: Cyr61 • Chondrosarcoma • MMP-13 • Integrin • Migration

Received July 22, 2008; revised November 5, 2008; accepted December 9, 2008.


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