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Gene expression profiling of pancreatic cancer cell line BxPC-3 induced by PAR-2 AP

ABSTRACT: Protease-activated receptor-2 (PAR-2), a G protein-coupled receptor activated by trypsin and coagulant factors, plays broad spectrum of physiological and pathological roles especially in cancer development. In this study, we used PAR-2 activating peptide to mimic the action of trypsin to trigger PAR-2 signaling pathway and effects of PAR-2 activation on gene expression in human pancreatic cancer cell line BxPC-3 investigated by microarray analysis. Through DAVID bioinformatic resources, we observed that activated PAR-2-mediated genes are summarized to two different pathways, renal cell carcinoma and NFkB pathway. In renal cell carcinoma pathway, activated PAR-2 dysregulated hypoxia-inducible factors and its target genes, including glucose transporter 1 (GLUT1), transforming growth factor-b (TGF-b) and vascular endothelial growth factor-A (VEGF-A). In addition, activated PAR-2 induced MAPK signaling and transcriptional factors, such as JUN, MAP2K1 and ETS1. The regulation of these genes by PAR-2 assumed that PAR-2 signaling was associated with cancer progression. On the other hand, activated PAR-2 upregulated interleukin-1b (IL-1b) and toll-like receptor 4 (TLR4) related with NFkB activation, which indicated that PAR-2 signaling may cause cancer-related inflammation. In conclusion, PAR-2 may be a factor to regulate cancer progression and inflammation. Two-condition experiment, control cells vs PAR-2 AP-treated cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Teng Che-Ming

PROVIDER: S-ECPF-GEOD-44827 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Streptozotocin (STZ), a glucosamine-nitrosourea compound, has potent genotoxic effects on pancreatic ?-cells and is frequently used to induce diabetes in experimental animals. Glucagon-like peptide-1 (GLP-1) has ?-cell protective effects and is known to preserve ?-cells from STZ treatment. In this study, we analyzed the mechanisms of STZ-induced diabetes and GLP-1-mediated ?-cell protection in STZ-treated mice. At 1 week after multiple low-dose STZ administrations, pancreatic ?-cells showed impaired insulin expression, while maintaining expression of nuclear Nkx6.1. This was accompanied by significant upregulation of p53-responsive genes in islets, including a mediator of cell cycle arrest, p21 (also known as Waf1 and Cip1). STZ treatment also suppressed expression of a wide range of genes linked with key ?-cell functions or diabetes development, such as G6pc2, Slc2a2 (Glut2), Slc30a8, Neurod1, Ucn3, Gad1, Isl1, Foxa2, Vdr, Pdx1, Fkbp1b and Abcc8, suggesting global ?-cell defects in STZ-treated islets. The Tmem229B, Prss53 and Ttc28 genes were highly expressed in untreated islets and strongly suppressed by STZ, suggesting their potential roles in ?-cell function. When a pancreas-targeted adeno-associated virus (AAV) vector was employed for long-term Glp-1 gene delivery, pancreatic GLP-1 expression protected mice from STZ-induced diabetes through preservation of the ?-cell mass. Despite its potent ?-cell protective effects, however, pancreatic GLP-1 overexpression showed limited effects on the global gene expression profiles in the islets. Network analysis identified the programmed-cell-death-associated pathways as the most relevant network in Glp-1 gene therapy. Upon pancreatic GLP-1 expression, upregulation of Cxcl13 and Nptx2 was observed in STZ-damaged islets, but not in untreated normal islets. Given the pro-?-cell-survival effects of Cxcl12 (Sdf-1) in inducing GLP-1 production in ?-cells, pancreatic GLP-1-mediated Cxcl13 induction might also play a crucial role in maintaining the integrity of ?-cells in damaged islets.

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Gene expression profiling of pancreatic cancer cell line BxPC-3 induced by PAR-2 AP

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