Identification of Cyclooxygenase-2 as a Major Actor of the Transcriptomic Adaptation of Endothelial and Tumor Cells to Cyclic Hypoxia: Effect on Angiogenesis and Metastases
Identification of Cyclooxygenase-2 as a Major Actor of the Transcriptomic Adaptation of Endothelial and Tumor Cells to Cyclic Hypoxia: Effect on Angiogenesis and Metastases
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DOI：
10.1158/1078-0432.ccr-09-0583
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发表时间：
2010-01-15
影响因子：
11.5
通讯作者：
Feron, Olivier
中科院分区：
文献类型：
--
作者：
Daneau, Geraldine;Boidot, Romain;Feron, Olivier
目的：肿瘤中的循环缺氧源于红细胞流量的异质性，不仅影响肿瘤细胞，还影响肿瘤血管内皮细胞。Po(2)的波动，特别是短暂的复氧期是否改变了众所周知的缺氧诱导因子(HIF)依赖的基因程序，目前尚不清楚。实验设计：我们比较了循环缺氧和持续缺氧下内皮细胞和肿瘤细胞的转录谱，以揭示在血管生成和转移方面可能存在的差异。结果：芯片分析鉴定出早期基因是由循环缺氧选择性地在内皮细胞中诱导的。其中，我们重点研究了Ptgs2，因为观察到的mRNA表达增加导致环氧合酶-2(COX-2；Ptgs2的蛋白产物)的表达和活性显著增加。HIF-1α被循环缺氧(尽管有复氧期)所稳定，并被棘霉素和针对小干扰RNA的HIF-1α所证实有利于COX-2的诱导。使用特定的COX-2抑制剂和针对小干扰RNA的专门的COX-2，我们证明了COX-2与循环缺氧赋予内皮细胞更高的存活率和血管生成潜力有关。结论：我们的研究证明，Ptgs2/COX-2是循环缺氧基因信号的一部分，并在很大程度上解释了暴露在pO2波动中的内皮细胞和肿瘤细胞的独特表型，从而为表达COX-2和其他循环缺氧反应基因的肿瘤集群提供了新的视角。临床癌症资源；16(2)；410-9。(C)2010年AACR。
Purpose: Cyclic hypoxia in tumors originates from heterogeneities in RBC flux and influences not only tumor cells but also endothelial cells lining tumor blood vessels. Whether pO(2) fluctuations, particularly transient reoxygenation periods, alter the well-known hypoxia-inducible factor (HIF)-dependent gene program is largely unknown.Experimental Design: We compared the transcriptomic profiles of endothelial and tumor cells exposed to cyclic hypoxia versus continuous hypoxia to uncover a possible differential effect on angiogenesis and metastases.Results: Microarray analyses identified early genes that were selectively induced by cyclic hypoxia in endothelial cells. Among them, we focused on PTGS2 because the observed increase in mRNA expression led to a significant increase in the expression and activity of cyclooxygenase-2 (COX-2; the protein product of PTGS2). HIF-1 alpha was shown to be stabilized by cyclic hypoxia (despite reoxygenation periods) and to favor COX-2 induction as validated by the use of echinomycin and HIF-1 alpha targeting small interfering RNA. Using a specific COX-2 inhibitor and a dedicated COX-2 targeting small interfering RNA, we documented that COX-2 accounted for the higher endothelial cell survival and angiogenic potential conferred by cyclic hypoxia. Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells.Conclusions: Our study documents that PTGS2/COX-2 is part of a cyclic hypoxia gene signature and largely accounts for the unique phenotype of endothelial and tumor cells exposed to fluctuations in pO2, thereby offering new perspectives for the clustering of tumors expressing COX-2 together with other cyclic hypoxia-responsive genes. Clin Cancer Res; 16(2); 410-9. (C)2010 AACR.