title: Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 201620, China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Wu
authors.affiliation: Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201620, P.R. China.
authors.forename: Cuncun
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China. wang_lei744@icloud.com.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China. wang_lei744@icloud.com.
authors.forename: Wang
authors.initials: W
authors.lastname: Lei
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China. jiao_f@yeah.net.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China. jiao_f@yeah.net.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiao
authors.affiliation: Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 650 New Songjiang Road, Shanghai, 201620, China. yzwlw@hotmail.com.|Shanghai Key Laboratory of Pancreatic Disease, Shanghai, 201620, China. yzwlw@hotmail.com.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Wang
mesh_terms: D015415:Biomarkers; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016329:Sp1 Transcription Factor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases