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Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the  SPINT1  gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of  Spint1  in  Apc  Min/+  mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the  Apc  Min/+  model in the presence or absence of  Spint1 . We observed that knockout of the  F2rl1  gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by  Spint1  deletion, but also reduced tumor formation in the presence of  Spint1 . Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in  Apc  Min/+ ‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.

cancer science

Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in  Apc  Min/+  mice