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Hepatocyte growth factor activator inhibitor\u20101 regulates type II transmembrane serine proteases that activate protease\u2010activated receptor\u20102 (PAR\u20102). We previously reported that deletion of\n                    <jats:italic>Spint1<\/jats:italic>\n                    in\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>Min\/+<\/jats:sup>\n                    mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor\u2010\u03baB signaling. In this study, we examined the role of PAR\u20102 in accelerating tumor formation in the\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>Min\/+<\/jats:sup>\n                    model in the presence or absence of\n                    <jats:italic>Spint1<\/jats:italic>\n                    . We observed that knockout of the\n                    <jats:italic>F2rl1<\/jats:italic>\n                    gene, encoding PAR\u20102, not only eliminated the enhanced formation of intestinal tumors caused by\n                    <jats:italic>Spint1<\/jats:italic>\n                    deletion, but also reduced tumor formation in the presence of\n                    <jats:italic>Spint1<\/jats:italic>\n                    . Exacerbation of anemia and weight loss associated with HAI\u20101 deficiency was also normalized by compound deficiency of PAR\u20102. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA\/p65, vascular endothelial growth factor expression, and vascular density in\n                    <jats:italic>Apc<\/jats:italic>\n                    <jats:sup>Min\/+<\/jats:sup>\n                    \u2010induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR\u20102, and that HAI\u20101 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR\u20102 activating proteases.\n                  <\/jats:p>","DOI":"10.1111\/cas.14335","type":"journal-article","created":{"date-parts":[[2020,1,30]],"date-time":"2020-01-30T03:31:55Z","timestamp":1580355115000},"page":"1193-1202","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Protease\u2010activated receptor\u20102 accelerates intestinal tumor formation through activation of nuclear factor\u2010\u03baB signaling and tumor angiogenesis in\n                    <i>Apc<\/i>\n                    <sup>Min\/+<\/sup>\n                    mice"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8210-5460","authenticated-orcid":false,"given":"Makiko","family":"Kawaguchi","sequence":"first","affiliation":[{"name":"Department of Pathology University of Miyazaki Miyazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miyazaki Miyazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-0451","authenticated-orcid":false,"given":"Hiroaki","family":"Kataoka","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miyazaki Miyazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Izumi","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Miyazaki Miyazaki 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