Zhao Qing-Tao, Yue Shu-Qiang, Cui Zhong, Wang Qi, Cui Xin, Zhai Hui-Hong, Zhang Li-Hui, Dou Ke-Feng
Department of Hepatobiliary Sugery, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, China.
Life Sci. 2007 Jan 9;80(5):484-92. doi: 10.1016/j.lfs.2006.09.038. Epub 2006 Oct 12.
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 PGE2 to CMs. Furthermore, Cox-2 inhibition by SC-58635 resulted in PGE2 reduction accompanied by the down-regulation of four PGE2 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. PGE2 as a vital angiogenic factor may act directly on endothelial cells to promote HuH-7-stimulated angiogenic process. Moreover, Cox-2/PGE2/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.
血管生成在肿瘤的发展和生长过程中起着至关重要的作用。本研究旨在探讨环氧化酶 - 2（Cox - 2）途径在肝细胞癌（HCC）血管生成调控中的潜在作用。我们通过选择性Cox - 2抑制剂（SC - 58635）或Cox - 2小干扰RNA（siRNA）抑制HCC细胞系HuH - 7中的Cox - 2表达。来自HuH - 7细胞的条件培养基（CMs）用于体外和体内血管生成测定。与未处理和阴性siRNA处理的HuH - 7细胞的CMs相比，SC - 58635和Cox - 2 siRNA处理的HuH - 7细胞的CMs在体外显著抑制人脐静脉内皮细胞（HUVECs）的增殖、迁移和分化，在体内抑制新生血管形成。向CMs中添加外源性前列腺素E2（PGE2）可部分逆转这些抑制作用。此外，SC - 58635对Cox - 2的抑制导致PGE2减少，同时四种PGE2受体（EP受体）亚型表达下调。用SC - 58635处理导致HCC中促血管生成因子如血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）、成纤维细胞生长因子2（FGF2）、血管生成素1（ANGPT1）和血管生成素2（ANGPT2）表达下调。在SC - 58635处理的HuH - 7细胞的CM中发现VEGF水平降低了约78%。我们的结果表明Cox - 2参与了HCC相关血管生成的调控。PGE2作为一种重要的血管生成因子，可能直接作用于内皮细胞以促进HuH - 7刺激的血管生成过程。此外，Cox - 2/PGE2/EP/VEGF途径可能也参与了HCC中的肿瘤血管生成。本研究为Cox - 2抑制剂治疗或化学预防HCC的临床研究提供了理论依据。
