Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells.
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.
Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom. martinta1@cf.ac.uk
Tracey A
TA
Martin
Robert E
RE
Mansel
Wen G
WG
Jiang
D001943:Breast Neoplasms / Q000098:blood supply; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D062726:Junctional Adhesion Molecules; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008934:Mitogens; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010750:Phosphoproteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D062826:Zonula Occludens-1 Protein
D015815:Cell Adhesion Molecules; C066855:HGF protein, human; D062726:Junctional Adhesion Molecules; D008565:Membrane Proteins; D008934:Mitogens; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D017228:Hepatocyte Growth Factor