Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer

• Published in: Scientific reports 2017-03, Vol.7 (1), p.470-470, Article 470
• Main Authors: Hu, Hai, Han, Ting, Zhuo, Meng, Wu, Lei-lei, Yuan, Cuncun, Wu, Lixia, Lei, Wang, Jiao, Feng, Wang, Li-Wei
• Format: Article
• Language: English
• Subjects: 14; 14/1; 45; 45/91; 631/67/2322; 631/67/327; 82; 82/51; 82/80; Biomarkers; Cell Line, Tumor; Computational Biology - methods; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humanities and Social Sciences; Humans; Models, Biological; multidisciplinary; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Receptor, Epidermal Growth Factor - metabolism; Science; Science (multidisciplinary); Signal Transduction; Sp1 Transcription Factor - metabolism; Transcriptional Activation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00288-4

Cyclooxygenase-2 (COX-2) was stated to be overexpression in various human malignancies associating with angiogenesis, metastasis and chemoresistence. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease displaying many of these characteristics. A common abnormality of PDAC is overexpression of specificity protein-1 (Sp1), which was said to correlate with malignant phenotypes of human cancers. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we found that Sp1 expression was positively correlated with that of COX-2 in PDAC, and that the inhibition or overexpression of Sp1 in PDAC cells leads to decreased or elevated COX-2 expression. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that elevated transcription of COX-2 requires Sp1 binding to sequence positions around −245/−240 of COX-2 promoter. Activated epidermal growth factor receptor (EGFR) and downstream p38 mitogen-activated protein kinase (p38-MAPK) were also profoundly altered in PDAC. The inhibition of EGFR/p38-MAPK signaling resulted in reduced Sp1 activation, decreased COX-2 and vascular endothelial growth factor (VEGF) expression. Thus, Sp1 could transcriptionally activate COX-2 expression in a process relies on activated EGFR/p38-MAPK signaling. Finally, we found that the inhibition of COX-2 leads to decreased angiogenesis in a process dependent on VEGF, which link COX-2 to angiogenesis in PDAC.