Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice
Section snippets
Materials and methods
Recombinant materials and measurement of NK4. Recombinant human HGF and NK4 were respectively purified from culture media of CHO cells, which stably secrete human HGF and NK4 [6], [18]. Concentration of NK4 in the plasma was determined using enzyme-linked immunosorbent assay (ELISA) kit for human HGF (B-Bridge International Inc., CA, USA). Because this ELISA system does not cross-react with mouse HGF, human NK4 can be specifically detectable in mouse tissues and plasma. Recombinant human NK4
Inhibition of HGF-induced cell scattering by NK4 expressed in COS-7 cells
We first tested whether NK4 expressed in mammalian cells using pCAGGS-NK4 plasmid would inhibit biological response driven by HGF-Met association. COS-7 cells were transfected with pCAGGS-NK4 plasmid and biological activity of NK4 in the conditioned medium was examined in cell scattering assay using MDCK cells (Fig. 1A). When 110 pM HGF was added to monolayer culture of MDCK cells, HGF induced dissociation and scattering of the cells (Fig. 1A(a) and (b)), however, recombinant NK4 inhibited MDCK
Discussion
Since HGF activates intracellular and extracellular events that lead to dissociation and invasion of cancer cells, the HGF-Met system is closely involved in acquisition of invasive and metastatic potentials [7], [8], [9], [10]. HGF decreases cadherin-mediated adhesiveness of cells [20], [21], and stimulates proteolytic breakdown of the extracellular matrix, through enhancing matrix metalloproteinase and urokinase-type plasminogen activator-dependent proteolytic network [7], [8], [9], [10], [11]
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Technology, Sports and Culture of Japan, and Grant for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan.
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