15d-PGJ2 decreases PGE2 synthesis in HBx-positive liver cells by interfering EGR1 binding to mPGES-1 promoter
15d-PGJ2 decreases PGE2 synthesis in HBx-positive liver cells by interfering EGR1 binding to mPGES-1 promoter
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DOI：
10.1016/j.bcp.2014.07.032
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发表时间：
2014-10-01
影响因子：
5.8
通讯作者：
Tang, Nanhong
中科院分区：
文献类型：
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作者：
Liu, Chong;Chen, Siyan;Tang, Nanhong
微粒体前列腺素E合成酶1（mPGES-1）是PGE（2）合成的终末调节因子。在各种人类癌症中，mPGES-1的表达通过刺激炎症因子而增加。但B型肝炎病毒（HBV）感染是否影响mPGES-1及其在肝细胞中的分子机制尚未研究。在本研究中，我们观察到mPGES-1在肝癌组织中的表达与HBVX蛋白（HBx）呈正相关，并且HBx增强了HL 7702肝细胞中mPGES-1启动子的活性。机制研究表明，HBx可以增加早期生长反应1（EGR 1）与mPGES-1启动子转录位点的结合。EGFR 1的过表达和敲低均不影响HL 7702-HBx细胞中环氧合酶2（考克斯-2）的转录和表达。我们还研究了一种PGE（2）抑制剂15-deoxy-Delta（12，14）-prostaglandin J（2）（15 d-PGJ（2））在HBx阳性肝细胞中调节mPGES-1表达的独特功能。15 d-PGJ（2）对考克斯-2表达无影响，但抑制EGFR 1-mPGES-1-PGE（2）轴表达。EGR 1与mPGES-1启动子的结合能力降低，HL 7702-HBx细胞中EGR 1与mPGES-1启动子的结合能力降低更明显。结果表明，EGR 1是HBx上调mPGES-1表达的特异性转录因子，靶向EGR 1可能有助于抑制HBV诱导的炎症向癌变的转变。(C)2014爱思唯尔公司All rights reserved.
Microsomal prostaglandin E synthase 1 (mPGES-1) is the terminal regulator of PGE(2) synthesis. The expression of mPGES-1 is increased by stimulating inflammatory factors in various human cancers. However, whether hepatitis B virus (HBV) infection affects mPGES-1 and its molecular mechanism in liver cells has not been studied. In this study, we observed that mPGES-1 expression was positively correlated with HBV X protein (HBx) in hepatocellular carcinoma cancerous tissue, and HBx enhanced the mPGES-1 promoter activity in HL7702 liver cells. Mechanistic investigations revealed that HBx can increase the early growth response 1 (EGR1) binding to the transcription site of mPGES-1 promoter. The overexpression and knockdown of EGR1 did not affect cyclooxygenase-2 (COX-2) transcription and expression in HL7702-HBx cells. We also investigated the unique function of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a kind of PGE(2) inhibitor, in the regulation of mPGES-1 expression in HBx-positive liver cells. In the presence of 15d-PGJ(2), the expression of COX-2 was unaffected, but that of the EGR1-mPGES-1-PGE(2) axis was inhibited. Moreover, the capacity of EGR1 binding to the mPGES-1 promoter decreased, and the change in HL7702-HBx cells was more significant. The results indicated that EGR1 is a specific transcription factor in the up-regulation of mPGES-1 expression by HBx, and targeting EGR1 may contribute to inhibiting the change from inflammation to HBV-induced cancer. (C) 2014 Elsevier Inc. All rights reserved.