Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc Min/+ mice - Université Paris Cité Access content directly
Journal Articles Cancer Science Year : 2020

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

Makiko Kawaguchi
Koji Yamamoto
  • Function : Author
Hiroaki Kataoka
Aya Izumi
  • Function : Author
Fumiki Yamashita
  • Function : Author
Takumi Kiwaki
  • Function : Author
Takahiro Nishida
  • Function : Author
Eric Camerer
Tsuyoshi Fukushima

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 ApcMin/+ 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 ApcMin/+ 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 ApcMin/+ -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.

Domains

Cancer

Dates and versions

hal-03906233 , version 1 (19-12-2022)

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Makiko Kawaguchi, Koji Yamamoto, Hiroaki Kataoka, Aya Izumi, Fumiki Yamashita, et al.. Protease‐activated receptor‐2 accelerates intestinal tumor formation through activation of nuclear factor‐κB signaling and tumor angiogenesis in Apc Min/+ mice. Cancer Science, 2020, 111 (4), pp.1193-1202. ⟨10.1111/cas.14335⟩. ⟨hal-03906233⟩

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