Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis
Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis
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环氧合酶-2 通路可能参与肝细胞癌相关血管生成。
DOI：
10.1016/j.lfs.2006.09.038
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发表时间：
2007-01-09
期刊：
影响因子：
6.1
通讯作者：
Dou, Ke-Feng
中科院分区：
文献类型：
--
作者：
Zhao, Qing-Tao;Yue, Shu-Qiang;Dou, Ke-Feng
血管生成在肿瘤的发展和生长中起着至关重要的作用。本研究旨在探讨环氧合酶-2(COX-2)通路在肝细胞癌血管生成调控中的作用。我们通过选择性COX-2抑制剂(SC-58635)或COX-2siRNA抑制肝癌细胞株HH-7中COX-2的表达。用HH-7细胞的条件培养液(CMS)进行体外和体内血管生成实验。与未经处理和阴性siRNA处理的HU-7细胞相比，SC-58635和COX-2siRNA处理的HH-7细胞的CMS在体外显著抑制了人脐静脉内皮细胞的增殖、迁移和分化，并在体内显著抑制了新生血管的形成。外源PGE(2)可部分逆转上述抑制作用。此外，SC-58635抑制COX-2可降低PGE(2)，同时下调四种PGE_1受体(EP受体)亚型。SC-58635可下调肝细胞癌组织中血管生成因子的表达。从SC-58635处理的CM中发现血管内皮生长因子水平降低了约78%。我们的结果提示COX-2参与了肝细胞癌相关血管生成的控制。PGE作为一种重要的血管生成因子，可能直接作用于内皮细胞，促进HH-7刺激的血管生成过程。此外，COX-2/PGE(2)/EP/VEGF通路可能也参与了肝细胞癌的肿瘤血管生成。这项研究为临床研究COX-2抑制剂治疗或化学预防肝癌提供了理论基础。(C)2006 Elsevier Inc.保留所有权利。
Angiogenesis plays a crucial role in tumor development and growth. The present study was carried out to investigate the potential involvement of the cyclooxygenase-2 (Cox-2) pathway in the regulation of angiogenesis in hepatocellular carcinoma (HCC). We inhibited Cox-2 expression in HCC cell line HuH-7 by selective Cox-2 inhibitor (SC-58635) or Cox-2 siRNA. Conditioned media (CMs) from HuH-7 cells were used in angiogenic assays in vitro and in vivo. Compared with CMs from untreated and negative siRNA treated HuH-7 cells, CMs from SC-58635 and Cox-2 siRNA treated HuH-7 dramatically suppressed the proliferation, migration, and differentiation of human umbilical vein endothelial cells (HUVECs) in vitro and neovascularization in vivo. These inhibitory effects could be partially reversed by the addition of exogenous PGE(2) to CMs. Furthermore, Cox-2 inhibition by SC-58635 resulted in PGE(2) reduction accompanied by the down-regulation of four PGE, receptor (EP receptor) subtypes. Treatment with SC-58635 led to the down-expression of proangiogenic factors such as VEGF, HGF, FGF2, ANGPT1 and ANGPT2 in HCC. An approximately 78% reduction of VEGF level has been found in the CM from SC-58635 treated HuH-7. Our results suggest an involvement of Cox-2 in the control of HCC-associated angiogenesis. PGE, as a vital angiogenic factor may act directly on endothelial cells to promote HuH-7 -stimulated angiogenic process. Moreover, Cox-2/PGE(2)/EP/VEGF pathway possibly also contributes to tumor angiogenesis in HCC. This study provides the rationale for clinical studies of Cox-2 inhibitors on the treatment or chemoprevention of HCC. (c) 2006 Elsevier Inc. All rights reserved.