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Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-?B signaling and tumor angiogenesis in ApcMin/+ mice.

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-?B 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.

SUBMITTER: Kawaguchi M

PROVIDER: S-EPMC7156842 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-κB signaling and tumor angiogenesis in Apc<sup>Min/+</sup> mice.

Kawaguchi Makiko M Yamamoto Koji K Kataoka Hiroaki H Izumi Aya A Yamashita Fumiki F Kiwaki Takumi T Nishida Takahiro T Camerer Eric E Fukushima Tsuyoshi T

Cancer science 20200224 4

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<sup>Min/+</sup> mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor-κB signali ...[more]

PMID: 31997435

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Project description:Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCMin/+ ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APCMin/+ mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

Dataset Information

Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-?B signaling and tumor angiogenesis in ApcMin/+ mice.

Publications

Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-κB signaling and tumor angiogenesis in Apc<sup>Min/+</sup> mice.

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