title: Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells.
abstract: Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. Despite the advances in surgical and medical management, the mechanisms underlying human osteosarcoma progression and metastasis remain to be elucidated. Gene expression profiles were compared by the cDNA microarray technique between two different human osteosarcoma sublines, MNNG/HOS and 143B, which differ greatly in spontaneous pulmonary metastatic potential. Here we report an enhanced expression of matrix metalloproteinase (MMP)-1 in the highly metastatic human osteosarcoma cell line 143B. Moreover, the in vitro invasion activity of 143B cells was MMP-1-dependent. The activator protein (AP)-1 binding site in the MMP-1 gene promoter was required for the constitutive expression of MMP-1 in 143B cells. Two AP-1 components, c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells. Mitogen-activated protein kinase pathways including the c-Jun NH(2)-terminal kinase and the extracellular signal-regulated kinase activate c-Jun and Fra-1 and thereby regulate c-Jun/Fra-1 mediated events, establishing the mitogen-activated protein kinase/AP-1/MMP-1 axis as important in 143B cells. These data suggest that MMP-1 plays a central role in osteosarcoma invasion. Accordingly, MMP-1 might be a biomarker and therapeutic target for invasive osteosarcomas and pulmonary metastases.
authors.affiliation: Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Kimura
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Rokkaku
authors.forename: Ralf
authors.initials: R
authors.lastname: Janknecht
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D017931:DNA Primers; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C522360:MMP1 protein, human