國家衛生研究院 NHRI:Item 3990099045/7287
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    題名: Activated PAR-2 regulates pancreatic cancer progression through ILK/HIF-alpha–induced TGF-alpha expression and MEK/VEGF-A–mediated angiogenesis
    其他題名: Activated PAR-2 regulates pancreatic cancer progression through ILK/HIF-α–induced TGF-α expression and MEK/VEGF-A–mediated angiogenesis
    作者: Chang, LH;Pan, SL;Lai, CY;Tsai, AC;Teng, CM
    貢獻者: Institute of Biotechnology and Pharmaceutical Research
    摘要: 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.
    日期: 2013-08
    關聯: American Journal of Pathology. 2013 Aug;183(2):566-575.
    Link to: http://dx.doi.org/10.1016/j.ajpath.2013.04.022
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0002-9440&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000322611700024
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84880634202
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