Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer.
Elevated COX-2 Expression Promotes Angiogenesis Through EGFR/p38-MAPK/Sp1-Dependent Signalling in Pancreatic Cancer.
复制标题
胰腺癌中 COX-2 表达升高通过 EGFR/p38-MAPK/Sp1 依赖性信号传导促进血管生成。
DOI：
10.1038/s41598-017-00288-4
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发表时间：
2017-03-28
影响因子：
4.6
通讯作者：
Wang LW
中科院分区：
文献类型：
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作者：
Hu H;Han T;Zhuo M;Wu LL;Yuan C;Wu L;Lei W;Jiao F;Wang LW
环氧合酶-2（Cyclooxygenase-2，考克斯-2）在多种恶性肿瘤中过度表达，与肿瘤的血管生成、转移和化疗耐药有关。胰腺导管腺癌（PDAC）是一种致命的疾病，表现出许多这些特征。PDAC的常见异常是特异性蛋白-1（Sp1）的过表达，据说其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PDAC中Sp1表达与考克斯-2表达正相关，并且PDAC细胞中Sp1的抑制或过表达导致考克斯-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）分析显示，考克斯-2的转录水平升高需要Sp1结合到考克斯-2启动子的−245/−240附近的序列位置。活化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）也在PDAC中发生了深刻的改变。抑制EGFR/p38-MAPK信号通路导致Sp1活化减少、考克斯-2和血管内皮生长因子（VEGF）表达减少。因此，Sp1可以转录激活考克斯-2的表达，其过程依赖于激活的EGFR/p38-MAPK信号。最后，我们发现，考克斯-2的抑制导致血管生成减少的过程中依赖于VEGF，其连接考克斯-2血管生成在PDAC。
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.