Nk4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells.
Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a heterodimeric molecule that plays a key role in the regulation of migration, invasion and angiogenesis in cancer, via activation of its receptor, c-met. HGF/SF is composed of an alpha-chain, containing the N-terminal hairpin domain and 4 kringle domains, plus the serine protease-like beta-chain. We have examined here the properties of NK4, an HGF variant containing the N-terminal hairpin plus the 4 kringle domains, on tumour cell proliferation, dissociation and invasion using human colorectal cancer cells (HT115). The expression of HGF/SF and its receptor was also examined by RT-PCR and Western blotting. Analysis revealed NK4 to be an HGF/SF antagonist that, at a wide range of concentrations, did not exert any biological effects of its own. HT115 cells were shown to express the HGF/SF receptor mRNA and protein. HGF/SF-induced receptor tyrosine phosphorylation was suppressed, in a dose-dependent manner, upon addition of NK4, whereas the addition of NK4 alone caused no phosphorylation. Tumour cell motility was induced by HGF and inhibited by NK4. Furthermore, HGF/SF induced the invasion of cells through Matrigel basement membrane components, and again this induced invasion was suppressed by NK4. Our results show that the ability of HGF/SF to stimulate tumour cell motility and invasion, properties required for metastatic spread, can be inhibited by NK4. Thus, NK4 may have an important role in the control of cancer metastasis.
Parr
C
C
University Department of Surgery, University of Wales College of Medicine, Cardiff, UK. Parrc@cf.ac.uk
Hiscox
S
S
Nakamura
T
T
Matsumoto
K
K
Jiang
W G
WG
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D015179:Colorectal Neoplasms / Q000473:pathology / Q000503:physiopathology; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met