https://scholars.lib.ntu.edu.tw/handle/123456789/477472
標題: | Involvement of hypoxia-inducing factor-1α-dependent plasminogen activator inhibitor-1 up-regulation in Cyr61/CCN1-induced gastric cancer cell invasion | 作者: | MING-TSAN LIN BEEN-REN LIN Chang C.-C. CHIA-YU CHU Chen H.-Y. Sureshbabu M. Shih H.-J. Kuo M.-L. |
公開日期: | 2008 | 卷: | 283 | 期: | 23 | 起(迄)頁: | 15807-15815 | 來源出版物: | Journal of Biological Chemistry | 摘要: | Cysteine-rich 61 (Cyr61/CCN1), one of the members of CCN family, has been implicated in the progression of human malignancies. Previously, our studies have demonstrated that Cyr61/CCN1 has a role in promoting gastric cancer cell invasion, but the mechanism is not clear yet. Here, we found that hypoxia-inducing factor-1α(HIF-1α) protein, but not mRNA, expression was significantly elevated in gastric cancer cells overexpressing Cyr61. Supportively, a profound reduction of endogenous HIF-1α protein was noted in one highly invasive cell line, TSGH, when transfected with antisense Cyr61. By comparison, the induction kinetics of HIF-1α protein by recombinant Cyr61 (rCyr61) was distinct from that of insulin-like growth factor-1 and CoCl2 treatment, both well known for induction of HIF-1α. Using cycloheximide and MG132, we demonstrated that the Cyr61-mediated HIF-1α up-regulation was through de novo protein synthesis, rather than increased protein stability. rCyr61 could also activate the PI3K/AKT/mTOR and ERK1/2 signaling pathways, both of which were essential for HIF-1α protein accumulation. Blockage of HIF-1α activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)-HIF-1α strongly inhibited their invasion ability, suggesting that elevation in HIF-1α protein is vital for Cyr61-mediated gastric cancer cell invasion. In addition, several HIF-1α-regulated invasiveness genes were examined, and we found that only plasminogen activator inhibitor-1 (PAI-1) showed a significant increase in mRNA and protein levels in cells overexpressing Cyr61. Treatment with PAI-1-specific antisense oligonucleotides or function-neutralizing antibodies abolished the invasion ability of the Cyr61-overexpressing cells. Transfection with dominant negative-HIF-1α to block HIF-1α activity also effectively reduced the elevated PAI-1 level. In conclusion, our data provide a detailed mechanism by which Cyr61 promoted gastric cancer cell invasive ability via an HIF-1α-dependent up-regulation of PAI-1. ? 2008 by The American Society for Biochemistry and Molecular Biology, Inc. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-47049116948&doi=10.1074%2fjbc.M708933200&partnerID=40&md5=b0f4f0314ca887efdabb3821c33ece44 https://scholars.lib.ntu.edu.tw/handle/123456789/477472 |
ISSN: | 0021-9258 | DOI: | 10.1074/jbc.M708933200 | SDG/關鍵字: | Cell culture; Growth kinetics; MOS capacitors; Nucleic acids; Oligonucleotides; Anti senses; Antisense oligonucleotides; Cell lines; Cycloheximide; Dominant negatives; Gastric cancer cells; Growth factors; Human malignancies; In cells; Induction kinetics; Invasiveness; Neutralizing antibodies; Novo proteins; Overexpressing cells; Plasminogen activator inhibitors; Protein accumulations; Protein levels; Protein stabilities; Signaling pathways; Cells; benzyloxycarbonylleucylleucylleucinal; cycloheximide; cysteine rich protein 61; hypoxia inducible factor 1alpha; mammalian target of rapamycin; mitogen activated protein kinase 1; mitogen activated protein kinase 3; plasminogen activator inhibitor 1; protein kinase B; somatomedin binding protein 1; antineoplastic agent; benzyloxycarbonylleucyl leucyl leucine aldehyde; benzyloxycarbonylleucyl-leucyl-leucine aldehyde; cobalt; cobalt chloride; cycloheximide; CYR61 protein, human; HIF1A protein, human; hypoxia inducible factor 1alpha; immediate early protein; leupeptin; messenger RNA; protein synthesis inhibitor; recombinant protein; signal peptide; tumor protein; article; cell invasion; controlled study; human; human cell; outcome assessment; priority journal; protein expression; protein induction; protein stability; protein synthesis; receptor upregulation; stomach cancer; biosynthesis; cancer invasion; drug effect; gene expression regulation; genetics; kinetics; metabolism; pathology; signal transduction; stomach tumor; tumor cell line; upregulation; Antineoplastic Agents; Cell Line, Tumor; Cobalt; Cycloheximide; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Kinetics; Leupeptins; MAP Kinase Signaling System; Neoplasm Invasiveness; Neoplasm Proteins; Plasminogen Activator Inhibitor 1; Protein Biosynthesis; Protein Synthesis Inhibitors; Recombinant Proteins; RNA, Messenger; Stomach Neoplasms; Up-Regulation |
顯示於: | 醫學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。