Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1.
Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1.
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发表时间：
2002-01
期刊：
影响因子：
11.2
通讯作者：
K. Sales;A. Katz;B. Howard;R. Soeters;R. Millar;H. Jabbour
中科院分区：
文献类型：
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作者：
K. Sales;A. Katz;B. Howard;R. Soeters;R. Millar;H. Jabbour
本研究旨在探讨环氧合酶-1(COX-1)在宫颈癌中的表达及其分子信号转导机制。实时定量逆转录聚合酶链式反应和Western印迹分析证实COX-1RNA和蛋白在宫颈鳞癌和腺癌中的表达增强。所有癌组织中COX-1的表达均与COX-2RNA和蛋白的表达增强有关。用免疫组织化学方法对所有鳞癌和腺癌的癌上皮细胞进行了COX-1表达的定位。正常宫颈组织中仅检测到极少量的COX-1免疫反应。为了探索与COX-1上调相关的事件，我们开发了一个多西环素调控的HeLa(宫颈癌)细胞表达系统。在HeLa细胞中过表达COX-1可诱导环氧合酶-2(COX-2)和前列腺素E合成酶(PGES)的表达，同时增加前列腺素E(2)(PGE(2))的合成。用双重COX酶抑制剂吲哚美辛或选择性COX-2抑制剂NS-398处理过表达COX-1的HeLa细胞，显著减少PGE(2)的合成。消炎痛而不是NS-398可阻断COX-2和PGES在HeLa细胞中的表达上调，提示COX-2和PGES的上调是由COX-1酶产物介导的。为了评估COX-1诱导后促进PGE(2)合成是否以自分泌/旁分泌的方式起作用，我们观察了COX-1对PGE(2)受体不同亚型(EP1-EP4)表达的影响。我们发现COX-1过表达显著上调了cAMP连接的PGE(2)受体，这与这些细胞对外源PGE(2)配体的cAMP反应性增强是一致的。最后，COX-1的过度表达与血管生成因子碱性成纤维细胞生长因子、血管内皮生长因子、血管生成素-1和血管生成素-2的表达增强有关。这种对血管生成因子表达的上调可被消炎痛取消，并被NS-398部分抑制。这些数据表明，COX-1上调调节了一些因子的表达，这些因子可能以自分泌/旁分泌的方式作用于肿瘤宫颈上皮细胞，以增强和维持肿瘤的发生。很可能类似的机制可能在体内作用于调节宫颈癌的发生。
This study was designed to investigate the expression and molecular signaling of cyclooxygenase-1 (COX-1) in cervical carcinomas. Real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis confirmed enhanced expression of COX-1 RNA, and protein in squamous cell carcinomas and adenocarcinoma of the cervix. COX-1 expression in all carcinoma tissues was associated with enhanced expression of COX-2 RNA and protein. The site of COX-1 expression was localized by immunohistochemistry to the neoplastic epithelial cells in all squamous cell carcinomas and adenocarcinomas studied. Minimal COX-1 immunoreactivity was detected in normal cervix. To explore events associated with COX-1 up-regulation, we developed a doxycycline-regulated expression system in HeLa (cervical carcinoma) cells. Overexpression of COX-1 in HeLa cells resulted in induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PGES) concomitant with increased prostaglandin E(2) (PGE(2)) synthesis. Treatment of HeLa cells overexpressing COX-1 with the dual COX enzyme inhibitor indomethacin or selective COX-2 inhibitor NS-398 significantly reduced PGE(2) synthesis. Indomethacin, but not NS-398, treatment abolished the up-regulation of expression of COX-2 and PGES in HeLa cells, suggesting that the observed up-regulation of COX-2 and PGES was mediated by COX-1-enzyme products. To assess whether enhanced PGE(2) synthesis after COX-1 induction would act in an autocrine/paracrine manner, we investigated the effect of COX-1 on the expression of the different isoforms of PGE(2) receptors (EP1-EP4). We found that the cAMP-linked PGE(2) receptors were significantly up-regulated by COX-1 overexpression coincident with enhanced cAMP responsiveness of these cells to exogenous PGE(2) ligand. Finally, overexpression of COX-1 was associated with enhanced expression of the angiogenic factors basic fibroblast growth factor, vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2. This up-regulation of angiogenic factor expression was abolished by indomethacin and partially reduced by NS-398. These data indicate that COX-1 up-regulation modulates the expression of factors that may act in an autocrine/paracrine manner to enhance and sustain tumorigenesis in neoplastic cervical epithelial cells. It is likely that similar mechanisms may act in vivo to modulate tumorigenesis of cervical carcinomas.