Hepatocyte growth factor/c-met signaling in regulating urokinase plasminogen activator in human stomach cancer: A potential therapeutic target for human stomach cancer.
BACKGROUND
Up-regulation of the hepatocyte growth factor (HGF), its transmembrane tyrosine kinase receptor (c-Met), and urokinase type plasminogen activator (uPA), is associated with the development and metastasis of various types of cancers. However, the mechanisms by which HGF/c-Met signaling mediates cancer progression and metastasis are unclear.


METHODS
We investigated the roles of HGF/c-Met in tumor progression and metastasis in NUGC-3 and MKN-28 stomach cancer cell lines.


RESULTS
Treatment with HGF increased c-Met phosphorylation in a dose-dependent manner, as well as increasing cell proliferation. HGF treatment also increased the protein level and the activity of uPA in NUGC-3 and MKN-28 cells. A monoclonal antibody against human uPA receptor (uPAR), 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 in NUGC-3 cells.


CONCLUSIONS
These results suggest that NUGC-3 and MKN-28 cells express functional c-Met, which may provide a therapeutic target for interfering with metastases of cancer cells by inhibiting uPA and uPAR-mediated proteolysis.
Lee
Kyung Hee
KH
Department of Hemato-oncology, Yeungnam University College of Medicine, Daegu, Korea.
Choi
Eun Young
EY
Hyun
Myung Soo
MS
Jang
Byung Ik
BI
Kim
Tae Nyeun
TN
Kim
Sang Woon
SW
Song
Sun Kyo
SK
Kim
Jung Hye
JH
Kim
Jae-Ryong
JR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D018450:Disease Progression; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000187:drug effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects*; D017978:Receptors, Growth Factor / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator