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Protease-activated receptor 2 (PAR2) alleviates intestinal inflammation by upregulating autophagy. PAR2 also modulates tight junctions through β-arrestin signaling. Therefore, we investigated the effect of PAR2-induced autophagy on intestinal epithelial tight junctions and permeability. RT-PCR, Western blot analysis, and immunoprecipitation were performed to investigate the underlying molecular mechanisms by which PAR2 regulates autophagy and intestinal epithelial tight junctions. Inhibition of PAR2 by GB83, a PAR2 antagonist, decreased the expression of autophagy-related and tight-junction-related factors in Caco-2 cells. Moreover, inhibition of PAR2 decreased intestinal transepithelial electrical resistance. When PAR2 was activated, intestinal permeability was maintained, but when autophagy was suppressed by chloroquine, intestinal permeability was significantly increased. In addition, the prolongation of ERK1/2 phosphorylation by PAR2–ERK1/2–β-arrestin assembly was reduced under autophagy inhibition conditions. Therefore, PAR2 induces autophagy to regulate intestinal epithelial permeability, suggesting that it is related to the β-arrestin–ERK1/2 pathway. In conclusion, regulating intestinal epithelial permeability through PAR2-induced autophagy can help maintain mucosal barrier integrity. Therefore, these findings suggest that the regulation of PAR2 can be a suitable strategy to treat intestinal diseases caused by permeability dysfunction. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy. [ABSTRACT FROM AUTHOR]