Activated PAR-2 Regulates Pancreatic Cancer Progression through ILK/HIF-α–Induced TGF-α Expression and MEK/VEGF-A–Mediated Angiogenesis

Abstract

Tissue factor initiates the process of thrombosis and activates cell signaling through protease-activated receptor-2 (PAR-2). The aim of this study was to investigate the pathological role of PAR-2 signaling in pancreatic cancer. We first demonstrated that activated PAR-2 up-regulated the protein expression of both hypoxia-inducible factor-1α (HIF-1α) and HIF-2α, resulting in enhanced transcription of transforming growth factor-α (TGF-α). Down-regulation of HIFs-α by siRNA or YC-1, an HIF inhibitor, resulted in depleted levels of TGF-α protein. Furthermore, PAR-2, through integrin-linked kinase (ILK) signaling, including the p-AKT, promoted HIF protein expression. Diminishing ILK by siRNA decreased the levels of PAR-2-induced p-AKT, HIFs-α, and TGF-α; our results suggest that ILK is involved in the PAR-2-mediated TGF-α via an HIF-α-dependent pathway. Furthermore, the culture medium from PAR-2-treated pancreatic cancer cells enhanced human umbilical vein endothelial cell proliferation and tube formation, which was blocked by the MEK inhibitor, PD98059. We also found that activated PAR-2 enhanced tumor angiogenesis through the release of vascular endothelial growth factor-A (VEGF-A) from cancer cells, independent of the ILK/HIFs-α pathways. Consistent with microarray analysis, activated PAR-2 induced TGF-A and VEGF-A gene expression. In conclusion, the activation of PAR-2 signaling induced human pancreatic cancer progression through the induction of TGF-α expression by ILK/HIFs-α, as well as through MEK/VEGF-A-mediated angiogenesis, and it plays a role in the interaction between cancer progression and cancer-related thrombosis.

Re: Shi et al. Protease‐activated receptor 2 suppresses lymphangiogenesis and subsequent lymph node metastasis in a murine pancreatic cancer model. J Pathol 2014;234: 398‐409

“…In addition to the well-known role of PAR-2 in the primary proliferation of various cancer cells [2,3], including pancreatic cancer [4], the results presented highlighted convincingly the importance of stromal host receptors relative to local progression in the orthotopic pancreatic cancer model. The authors recorded an increase in the average volume of primary tumours in wild-type animals compared with PAR-2 −/− knockouts.…”

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.…”

Vascular Endothelial Growth Factor (VEGF), Mast Cells and Inflammation

“…These growth factors form homo-or heterodimers, stimulate cell surface receptors which activate the major signaling transduction pathways like the Ras-mitogen activated protein kinase pathway, and act as potent mitogens and chemoattractants for smooth muscle cells, fibroblasts and endothelial cells (72)(73)(74)(75). Responses to VEGF include inflammation, cellular proliferation, migration and resistance to apoptosis.…”