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.
原文 | 英語 |
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頁(從 - 到) | 566-575 |
頁數 | 10 |
期刊 | American Journal of Pathology |
卷 | 183 |
發行號 | 2 |
DOIs | |
出版狀態 | 已發佈 - 8月 2013 |
ASJC Scopus subject areas
- 病理學與法醫學
指紋
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Gene expression profiling of pancreatic cancer cell line BxPC-3 induced by PAR-2 AP
Chang, L.-H. (Contributor), Pan, S.-L. (Contributor), Lai, C.-Y. (Contributor), Tsai, A.-C. (Contributor) & Teng, C.-M. (Contributor), Gene Expression Omnibus, 2013
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44827
資料集: Dataset