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Cyr61 increases migration and MMP-13 expression via {alpha}v{beta}3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells |
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| Authors: | Tan, Tzu-Wei Yang, Wei-Hung Lin, Yuh-Tzy Hsu, Sheng-Feng Li, Te-Mao Kao, Shung-Te Chen, Wen-Chi Fong, Yi-Chin Tang, Chih-Hsin |
| Affiliation: | 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 |
| Abstract: | Cysteine-rich 61 (Cyr61), from the CCN gene family, is a secretedand matrix-associated protein, which is involved in many cellularactivities such as growth and differentiation. However, theeffect of Cyr61 on migration activity in human chondrosarcomacells is mostly unknown. Here, we found that Cyr61 increasedthe migration and expression of matrix metalloproteinase (MMP)-13in human chondrosarcoma cells (JJ012 cells). RGD peptide,  vβ3monoclonal antibody and mitogen-activated protein kinase (MEK)inhibitors (PD98059 and U0126) but not RAD peptide inhibitedthe Cyr61-induced increase of the migration and MMP-13 upregulationof chondrosarcoma cells. Cyr61 stimulation increased the phosphorylationof focal adhesion kinase (FAK) and extracellular signal-regulatedkinase (ERK). In addition, activator protein-1 (AP-1) decoyoligodeoxynucleotide also suppressed the MMP-13 messenger RNAand enzyme activity enhanced by Cyr61. Moreover, Cyr61 increasedthe binding of c-Fos and c-Jun to the AP-1 element on the MMP-13promoter. Taken together, our results indicated that Cyr61 enhancesthe migration of chondrosarcoma cells by increasing MMP-13 expressionthrough the vβ3 integrin receptor, FAK, ERK, c-Fos/c-Junand 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 |
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