Open AccessProtease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc Min/+ mice
Author(s) -
Kawaguchi Makiko,
Yamamoto Koji,
Kataoka Hiroaki,
Izumi Aya,
Yamashita Fumiki,
Kiwaki Takumi,
Nishida Takahiro,
Camerer Eric,
Fukushima Tsuyoshi
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14335
Subject(s) - proteases , biology , angiogenesis , cancer research , vascular endothelial growth factor , hepatocyte growth factor , serine protease , signal transduction , microbiology and biotechnology , carcinogenesis , vascular endothelial growth inhibitor , protease , receptor , chemistry , vascular endothelial growth factor a , biochemistry , enzyme , gene , vegf receptors
Abstract 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.