title: c-Jun NH2-terminal kinase pathway is involved in constitutive matrix metalloproteinase-1 expression in a hepatocellular carcinoma-derived cell line.
abstract: Transcription factor c-Jun serves for cellular proliferation, survival, differentiation and transformation and is recognized as an important factor in cancer development, including hepatocellular carcinoma (HCC). The purpose of present study is to determine the involvement of c-Jun in matrix metalloproteinase-1 (MMP-1) expression, which is previously reported by us to be expressed only in the early stage of human HCC showing stromal invasion. Of 5 human HCC cell lines examined, only HLE cells revealed mRNA and protein expression as well as enzymatic activity of MMP-1. Transient transfection of an MMP-1 promoter/luciferase construct (including 4.4 kb full promoter region) into HLE and HCC-T cells (MMP-1 nonproducer) showed that high promoter activity was observed only in HLE cells without inducers, and that this promoter activity was still observed when a shorter 0.6 kb proximal promoter construct was transfected. The 0.6 kb promoter region contained 3 AP-1 sites, and c-jun mRNA was constitutively expressed in HLE cells without inducers. Furthermore, phosphorylated c-Jun and c-Jun NH2-terminal kinase (JNK) were detected in HLE cells. Promoter activity of the 0.6 kb construct was suppressed with SP600125, a potent inhibitor of JNK, but not with PD98059 and SB203580, potent inhibitors of MEK1/2 and p38, respectively. The inhibitory effect of SP600125 was also observed at protein expression level and in enzymatic activity of MMP-1. Taken together, this study suggests that the JNK pathway is involved in the expression of MMP-1 in HCC cells and may represent a new functional role of c-Jun for HCC development.
authors.affiliation: Department of Community Health, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sugioka
authors.forename: Tetsu
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Miwa
authors.initials: M
authors.lastname: Kushida
authors.forename: Maki
authors.initials: M
authors.lastname: Niioka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endo
authors.forename: Reiichi
authors.initials: R
authors.lastname: Higashiyama
authors.forename: Isao
authors.initials: I
authors.lastname: Okazaki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D016762:Genes, fos / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D008156:Luciferases; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1