title: 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.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Li-Hsun
authors.initials: LH
authors.lastname: Chang
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Tsai
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000502:physiology; D007191:Indazoles / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000209:etiology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D034741:RNA, Small Interfering / Q000502:physiology; D044464:Receptor, PAR-2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D000099200:Scaffold Protein ILK; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005419:Flavonoids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D000099200:Scaffold Protein ILK; D000099162:Endothelial PAS Domain-Containing Protein 1; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one