Protease-activated receptor-2 induces expression of vascular endothelial growth factor and cyclooxygenase-2 via the mitogen-activated protein kinase pathway in gastric cancer cells

Abstract

Protease-activated receptor-2 (PAR-2) has shown strong pro-angiogenesis activity physiologically and pathologically. This study aimed to explore PAR-2 regulation of pro-angiogenesis gene expression and the underlying molecular pathways in gastric cancer cells. MKN28 human gastric cancer cells were treated with trypsin, a PAR-2 activator, and subjected to real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting and ELISA for gene expression analyses. ERK1/2 phosphorylation and p38 MAP kinase inhibitors (PD98059 and SB203580, respectively) were used to block their gene activities. PAR-2 mRNA and protein were expressed in MKN-28 cells and activated by trypsin treatment. Trypsin-activated PAR-2 protein significantly enhanced expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) mRNA and protein in gastric cancer cells in a dose- and time-dependent manner. PAR-2 activation also induced the phosphorylation of ERK1/2 and p38 MAP kinase, but the ERK1/2 and p38 inhibitors blocked the activated PAR-2-induced VEGF and COX-2 expression in gastric cancer cells. PAR-2-induced expression of VEGF and COX-2 mRNA and protein in gastric cancer MKN28 cells was mediated by activation of an ERK1/2- and p38 MAP kinase-dependent pathway. Thus, PAR-2 may serve as a promising target for anti-angiogenesis therapy to treat gastric cancer.

Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer

“…PAR-2 expression/activation has been described in a number of human epithelial malignancies [14, 15, 34] and triggers growth factor/chemokine release from malignant cells, including IL-6 [14], IL-8 [12], and VEGF [13]. PAR-2 activation in EOC may similarly impact the peritoneal microenvironment [35].…”

“…Likewise, PAR-2 signaling is associated with a promigratory, invasive, and proangiogenic phenotype in experimental models of breast cancer [11–13]. PAR-2 activation and induction of growth factor/chemokine expression, including prominently vascular endothelial growth factor (VEGF), has been described in renal cell carcinoma and colon cancer cell lines [14, 15]. Thus, the TF/FVIIa/PAR-2 axis may directly contribute to the progression of malignancy.…”

Mast Cells Density Positive to Tryptase Correlate with Microvascular Density in both Primary Gastric Cancer Tissue and Loco-Regional Lymph Node Metastases from Patients That Have Undergone Radical Surgery

“…Tryptase is an agonist of PAR-2 in vascular ECs that stimulates their proliferation. Signaling via PAR-2 on ECs elicits activation of the major members of the MAPK phosphorylation family and contributes to proliferation of ECs and angiogenesis [23,24,25,26,27,28,29,30,31,32,47,48,49,50,51]. …”

“…So far, few data have been published on the relationship among MCs density positive to tryptase (MCDPT), and microvascular density (MVD) in both primary gastric cancer (GC) tissue and loco-regional lymph node metastases (LRLNM) [6,28,29,30,31,32]. …”

Tumour progression and cancer-induced pain: A role for protease-activated receptor-2?

“…3), a potent angiogenic factor, by these cells (Chang et al, 2013;Dutra-Oliveira et al, 2012;Liu and Mueller, 2006;Zhang et al, 2012). Furthermore, these studies reported that activation of PAR 2 by either trypsin or PAR 2 -activating peptides resulted in signalling via a number of pathways, including PI3K-dependent Akt pathways and ERK1/2 and p38 MAPK pathways.…”