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

Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma

“…Moreover, the results of external validation based on five GEO datasets and prognostic meta-analysis all confirmed the relatively better robustness of the prognostic signature compared to previous studies (9,37). F2RL1, also known as protease-activated receptor 2 (PAR2), has been reported to be associated with the occurrence and development of lung adenocarcinoma (44) and intestinal tumors (45,46). A recent study revealed that hypomethylation of the F2RL1 promoter could upregulate its expression and promote the proliferation, migration, and invasion of LUAD cells (44).…”

“…F2RL1 , also known as protease-activated receptor 2 ( PAR2 ), has been reported to be associated with the occurrence and development of lung adenocarcinoma ( 44 ) and intestinal tumors ( 45 , 46 ). A recent study revealed that hypomethylation of the F2RL1 promoter could upregulate its expression and promote the proliferation, migration, and invasion of LUAD cells ( 44 ).…”

Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

“…The clinicopathological findings are further supported by work in vitro and in model systems: LX-2 hepatic stellate cells-expressing F2RL1 enhance tumor growth via angiogenesis in vivo using a xenograft of hepatocellular carcinoma model [ 60 ] and in an intestinal tumor model [ 61 ]. In a mouse model of mammary tumor virus-polyoma middle T (PyMT), F2RL1 (PAR2), but not F2R (PAR1), signaling accelerates angiogenesis and tumor growth [ 62 ].…”

Mast Cells Mediate Inflammatory Injury and Aggravate Neurological Impairment in Experimental Subarachnoid Hemorrhage Through Microglial PAR-2 Pathway

“…Among the multiple participants, proteinase-activated receptor 2 (PAR-2) is one of the most important MCs-microglial interaction-related receptors. PAR-2, also known as GPR11 or F2RL1, belongs to the 7-transmembrane receptors that couple to guanosine-nucleotide-binding proteins family that are encoded by F2RL1 gene ( Kawaguchi et al, 2020 ). PAR-2 is widely expressed in mammals, especially in epidermal keratinocytes and immune cells, including neutrophils, dendritic cells, T cells, and macrophages ( Sutherland et al, 2019 ; Shah et al, 2020 ).…”