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.
Sci Rep. 2017 Mar 28;7(1):470. 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.
环氧化酶-2（COX-2）在与血管生成、转移和化疗耐药性相关的各种人类恶性肿瘤中表达过度。胰腺导管腺癌（PDAC）是一种具有多种这些特征的致命疾病。PDAC 的常见异常是特异性蛋白-1（Sp1）的过度表达，据说这与人类癌症的恶性表型相关。使用来自癌症基因组图谱（TCGA）的 RNA-seq 数据，我们发现 Sp1 表达与 PDAC 中的 COX-2 呈正相关，并且 PDAC 细胞中 Sp1 的抑制或过表达导致 COX-2 表达降低或升高。荧光素酶报告基因和染色质免疫沉淀（ChIP）测定显示，COX-2 的转录升高需要 Sp1 结合 COX-2 启动子周围-245/-240 的序列位置。激活的表皮生长因子受体（EGFR）和下游 p38 丝裂原活化蛋白激酶（p38-MAPK）在 PDAC 中也发生了深刻改变。EGFR/p38-MAPK 信号通路的抑制导致 Sp1 激活减少，COX-2 和血管内皮生长因子（VEGF）表达降低。因此，Sp1 可以在依赖于激活的 EGFR/p38-MAPK 信号通路的过程中转录激活 COX-2 表达。最后，我们发现 COX-2 的抑制导致依赖于 VEGF 的血管生成减少，这将 COX-2 与 PDAC 中的血管生成联系起来。
