title: Role of hepatocyte growth factor/c-Met signaling in regulating urokinase plasminogen activator on invasiveness in human hepatocellular carcinoma: a potential therapeutic target.
abstract: Hepatocyte growth factor (HGF), its transmembrane tyrosine kinase receptor (c-Met), and urokinase type plasminogen activator (uPA) is a key protein in the plasminogen activation system, which plays a proteolytically important role in the invasion and metastasis of various types of cancers. However, the mechanisms by which HGF/c-Met signaling mediates cancer progression and metastasis are unclear. This study was designed to investigate the roles of HGF/c-Met in tumor progression and metastasis in HepG2 and Hep3B hepatoma cell lines. Treatment with HGF increased c-Met phosphorylation in a dose-dependent manner. Activity of c-Met phosphorylation peaked 1-3 min after HGF treatment and then declined. HGF enhanced the protein level and the activity of uPA in HepG2 and Hep3B cells, and the uPAR protein level also increased in a HGF dose-dependent manner. HGF increased cell invasion through the Matrigel. A monoclonal antibody against human uPA receptor, mAb 3936, inhibited HGF-mediated tumor cell invasion in a dose-dependent manner. Down-regulation of uPA using uPA-shRNA induced a decrease in in vitro cell invasion. These results suggest that hepatoma cells express functional c-Met, which may provide a target for a therapeutic basis to interfere with metastases of cancer cells by inhibiting uPA system-mediated proteolysis.
authors.affiliation: Department of Hemato-Oncology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Hyun
authors.forename: Byung Ik
authors.initials: BI
authors.lastname: Jang
authors.forename: Tae Nyeun
authors.initials: TN
authors.lastname: Kim
authors.forename: Heon Ju
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jong Yuel
authors.initials: JY
authors.lastname: Eun
authors.forename: Hong Gin
authors.initials: HG
authors.lastname: Kim
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Yoon
authors.forename: Dong Sik
authors.initials: DS
authors.lastname: Lee
authors.forename: Jung Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator