Korean J Intern Med.  2006 Mar;21(1):20-27. 10.3904/kjim.2006.21.1.20.

Hepatocyte Growth Factor/c-Met Signaling in Regulating Urokinase Plasminogen Activator in Human Stomach Cancer: A Potential Therapeutic Target for Human Stomach Cancer

• Lee KH
• Choi EY
• Hyun MS
• Jang BI
• Kim TN
• Kim SW
• Song SK
• Kim JH
• Kim JR

• KMID: 1782247
• DOI: http://doi.org/10.3904/kjim.2006.21.1.20

Abstract

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.

Keyword

Metastasis; uPA; uPAR inhibition; Invasion

MeSH Terms

Urinary Plasminogen Activator/antagonists & inhibitors/*metabolism
Stomach Neoplasms/drug therapy/*enzymology
Signal Transduction/*drug effects
Receptors, Growth Factor/*drug effects
Receptor Protein-Tyrosine Kinases/*drug effects
Proto-Oncogene Proteins c-met/*drug effects
Neoplasm Metastasis
Humans
Hepatocyte Growth Factor/*metabolism
Disease Progression
Adenocarcinoma/drug therapy/enzymology