Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis
Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis
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DOI：
10.1093/carcin/bgp326
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发表时间：
2010-03-01
期刊：
影响因子：
4.7
通讯作者：
Nakagawa, Hiroshi
中科院分区：
文献类型：
--
作者：
Lee, James J.;Natsuizaka, Mitsuteru;Nakagawa, Hiroshi
低氧诱导因子（HIF），特别是HIF-1 α，与肿瘤生物学有关。然而，食管肿瘤微环境中的HIF靶基因仍然难以捉摸。对缺氧暴露的非转化的永生化人食管上皮细胞EPC 2-hTERT进行基因表达谱分析，并与食管鳞状细胞癌（ESCC）的基因特征进行比较。除了已知的HIF-1 α靶基因如碳酸酐酶9、胰岛素样生长因子结合蛋白3（IGFBP 3）和环氧合酶（考克斯）-2外，前列腺素E合酶（PTGES）被鉴定为ESCC以及暴露于缺氧的细胞中通常上调的新靶基因。在常氧条件下通过低氧或氯化钴稳定HIF-1 α后，PTGES诱导增强，并被显性负性HIF-1 α抑制。而PTGES信使RNA（mRNA）的负调控常氧，PTGES蛋白保持稳定后复氧。通过PTGES的异位表达以及针对PTGES的RNA干扰，在转化的人食管细胞中记录了前列腺素E-2（PGE（2））的生物合成。此外，缺氧刺激PGE（2）的生产在HIF-1 α依赖的方式。在食管鳞癌中，PTGES在mRNA和蛋白水平频繁过表达。最后，考克斯-2和PTGES与HIF-1 α和IGFBP 3共同定位于原发性肿瘤中。原发性肿瘤中考克斯-2-PTGES轴的激活通过伴随的白细胞介素-1 β的上调和羟基前列腺素脱氢酶的下调进一步证实。因此，PTGES是一种新的HIF-1 α靶基因，参与食管肿瘤缺氧微环境中前列腺素E的生物合成，这对不同类型的肿瘤，特别是鳞状起源的肿瘤有影响。
Hypoxia-inducible factors (HIFs), in particular HIF-1 alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1 alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1 alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1 alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E-2 (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1 alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1 alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1 beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1 alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.