Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13.
Chondrosarcoma is a low-grade sarcoma characterized by developing metastases and high local recurrence rate. Bone morphogenetic protein-2 (BMP-2) plays an essential role in tumor progression and metastasis. Here we found that BMP-2 induced the migration of human chondrosarcoma cells (JJ012 cells). BMP-2 also increased the secretion of metalloproteinase-13 (MMP-13) in JJ012 cells, as shown by reverse transcriptase-polymerase chain reaction, western blot and zymographic analysis. The MMP-13 small interfering RNA inhibited the BMP-2-induced MMP-13 expression and thereby significantly inhibited the BMP-2-induced cell migration. Furthermore, phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor suppressed BMP-2-induced MMP-13 mRNA expression. Transient transfection with dominant negative p85 and Akt mutant also showed that the PI3K/Akt signaling pathway was involved in BMP-2-induced MMP-13 expression. In addition, AP-1 decoy oligodeoxynucleotide also suppressed the MMP-13 promoter activity enhanced by BMP-2. Moreover, BMP-2 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 BMP-2 enhanced the invasiveness of chondrosarcoma cells by increasing MMP-13 expression through the PI3K, Akt, c-Fos/c-Jun and AP-1 signal transduction pathway.
Hou
Chun-Han
CH
Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; Department of Orthopedic Surgery, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin County, Taiwan.
Hsiao
Yu-Chun
YC
Fong
Yi-Chin
YC
Tang
Chih-Hsin
CH
D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002813:Chondrosarcoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D055396:Bone Morphogenetic Protein 2; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053509:Matrix Metalloproteinase 13