Expression of hepatocyte growth factor activator inhibitor type 1 on the epithelial cell surface is regulated by hypoxic and oxidative stresses

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/spint-1 is a membrane-bound protease inhibitor that is thought to regulate the activities of hepatocyte growth factor activator, matriptase, hepsin, and prostasin. In this study, we show that the membrane form of HAI-1 was significantly upregulated immunohistochemically in epithelial cells under adverse conditions including tissue injury, necroinflammatory reactions, and invasion of carcinomas. To analyze the mechanism underlying these in vivo observations, we examined the effects of hypoxia and oxidative stress on HAI-1 expression in vitro, using three human cell lines, HLC-1, WiDr, and HeLa. Hypoxic condition significantly enhanced the expression of HAI-1 in these cells. Oxidative stress also enhanced HAI-1 expression. Promoter analyses of the human HAI-1/spint-1 gene revealed overlapping binding site for Egr-1-3 and Sp1 near the transcription start site as the key domain for HAI-1/spint-1 transcription. This site was also critical in both hypoxic- and oxidative stress-induced HAI-1 upregulation. In fact, in vivo immunohistochemical studies indicated that areas with HAI-1 upregulation tended to express markers associated with hypoxia and oxidative stress. These observations suggest that the tissue microenvironment regulates the cell surface expression of HAI-1, and thereby may regulate proteolysis and processing of bioactive molecules on the cellular surface.