EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas
EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas
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DOI：
10.1158/0008-5472.can-07-0141
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Shu, Hui-Kuo G.
中科院分区：
文献类型：
--
作者：
Xu, Kaiming;Shu, Hui-Kuo G.
环氧合酶-2(COX-2)的表达与许多癌症有关，并可能与恶性表型有关，包括促进增殖、血管生成和对细胞毒治疗的抵抗。恶性胶质瘤是一种高度侵袭性的脑瘤，表现出这些特征中的许多。在这些星形细胞脑瘤中发现的一个显著的分子异常是表皮生长因子受体(EGFR)通过基因扩增和/或突变而改变，导致该受体的过度信号。我们发现EGF介导的EGFR酪氨酸激酶在人脑胶质瘤细胞系中的刺激可以诱导COX-2mRNA和蛋白的表达。P38丝裂原活化蛋白激酶(p38-MAPK)通路是这种激活的一个强大的下游因素，该通路的抑制导致了对COX-2诱导的强烈抑制。P38-MAPK途径可以激活Sp1/SP3转录因子，这似乎是依赖EGFR的COX-2启动子反式激活所必需的。对COX-2启动子/荧光素酶结构的分析表明，EGFR对COX-2启动子的转录激活需要Sp1结合位点位于-245/-240。此外，在体外和体内，EGFR的激活都能增强Sp1/SP3与启动子中这个位点的结合。Sp1/SP3增强DNA结合需要p38-MAPK活性，并与Sit转录因子的磷酸化增加相关。因此，恶性胶质瘤中EGFR的激活可以转录激活COX-2的表达，这一过程需要p38-MAPK和Sp1/SP3。最后，用COX-2活性的主要产物前列腺素E2处理胶质瘤细胞系，会导致血管内皮生长因子表达增加，从而可能将COX-2表达的升高与恶性胶质瘤的肿瘤血管生成联系起来。
Expression of cyclooxygenase-2 (COX-2) has been linked to many cancers and may contribute to malignant phenotypes, including enhanced proliferation, angiogenesis, and resistance to cytotoxic therapies. Malignant gliomas are highly aggressive brain tumors that display many of these characteristics. One prominent molecular abnormality discovered in these astrocytic brain tumors is alteration of epidermal growth factor (EGF) receptor (EGFR) through gene amplification and/or mutation resulting in excessive signaling from this receptor. We found that EGF-mediated stimulation of EGFR tyrosine kinase in human glioma cell lines induces expression of both COX-2 mRNA and protein. The p38 mitogen-activated protein kinase (p38-MAPK) pathway was a strong downstream factor in this activation with inhibition of this pathway leading to strong suppression of COX-2 induction. The p38-MAPK pathway can activate the Sp1/Sp3 transcription factors and this seems necessary for EGFR-dependent transactivation of the COX-2 promoter. Analysis of COX-2 promoter/luciferase constructs revealed that transcriptional activation of the COX-2 promoter by EGFR requires the Sp1 binding site located at -245/-240. Furthermore, Sp1/Sp3 binding to this site in the promoter is enhanced by EGFR activation both in vitro and in vivo. Enhanced DNA binding by Sp1/Sp3 requires p38-MAPK activity and correlates with increased phosphorylation of the Slit transcription factor. Thus, EGFR activation in malignant gliomas can transcriptionally activate COX-2 expression in a process that requires p38-MAPK and Sp1/Sp3. Finally, treatment of glioma cell lines with prostaglandin E2, the predominant product of COX-2 activity, results in increased vascular endothelial growth factor expression, thus potentially linking elevations in COX-2 expression with tumor angiogenesis in malignant gliomas.