Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells

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Abstract
Hepatocyte growth factor/scatter factor (HGF/SF) is a multi‐function cytokine that has been shown to regulate the expression of cell adhesion molecules in human endothelial cells. It is also a key cytokine in the development and progression of cancer, particularly during metastasis. NK4 is a variant of HGF/SF that has already been shown to be antagonistic to HGF/SF. This study shows that HGF/SF decreased transendothelial resistance (TER) and increased paracellular permeability in human vascular endothelial cells can that such effects can be inhibited by addition of the NK4 variant. In addition, HGF/SF‐stimulated invasion of endothelium by breast cancer cells was inhibited by the addition of NK4. Western blotting revealed that HGF/SF decreased the protein level, and increased tyrosine phosphorylation of ZO‐1, but did not cause a change in level of occludin or claudin‐1, both molecules involved in tight junction function. RT‐PCR revealed that addition of HGF/SF caused no change in signal for claudin‐5 or junctional adhesion molecule (JAM), but there was a decrease in the signal for claudin‐1. NK4 was able to prevent the decrease in levels of ZO‐1 protein by HGF/SF.