Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cells
Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cells
复制标题
通过小干扰 RNA 靶向肿瘤细胞中的 Rac1 GTPase 抑制内皮细胞增殖。
DOI：
10.1016/j.bbrc.2004.06.088
复制
发表时间：
2004-08-06
影响因子：
3.1
通讯作者：
Fan, DM
中科院分区：
文献类型：
--
作者：
Xue, Y;Bi, F;Fan, DM
缺氧诱导的血管生成在实体瘤的恶性过程中发挥着重要作用。最近包括我们自己在内的许多研究表明，Rho 家族小 GTP 酶参与了这一过程，而 Rho 家族的重要成员 Rac1 可能在调节缺氧诱导的多种血管生成因子和肿瘤抑制因子的基因激活中发挥着关键作用。为了进一步明确Rac1在血管生成中的功能并探索调节血管生成的新方法，我们采用小干扰RNA技术来敲低表达高水平Rac1的胃癌细胞系AGS中Rac1的基因表达。转染 Rac1 特异性 siRNA 载体后，AGS 细胞中 Rac1 的 mRNA 和蛋白水平均显着降低。当将来自Rac1下调的AGS细胞的条件培养基应用于人内皮细胞时，可以显着抑制细胞增殖。进一步的研究证明，在Rac1 siRNA转染的细胞中，两种血管生成促进因子VEGF和HIF-1α的表达下调，而肿瘤抑制因子和血管生成抑制因子p53和VHL的表达上调。我们的研究结果表明，Rac1可能通过控制血管生成相关因子的表达参与血管生成，并为靶向Rac1 GTPase治疗肿瘤血管生成提供了可能的策略。 (C) 2004 Elsevier Inc. 保留所有权利。
Hypoxia-induced angiogenesis plays an important role in the malignancy of solid tumors. A number of recent studies including our own have suggested that Rho family small GTPases are involved in this process, and Rac1, a prominent member of the Rho family, may be critical in regulating hypoxia-induced gene activation of several angiogenesis factors and tumor suppressors. To further define Rac1 function in angiogenesis and to explore novel approaches to modulate angiogenesis, we employed the small interference RNA technique to knock down gene expression of Rac1 in gastric cancer cell line AGS that expresses a high level of Rac1. Both the mRNA and protein levels of Rac1 in the AGS cells were decreased dramatically after transfection with a Rac1-specific siRNA vector. When the conditioned medium derived from the Rac1 downregulated AGS cells was applied to the human endothelial cells, it could significantly inhibit the cell proliferation. Further study proved that, VEGF and HIF-1alpha, two angiogenesis promoting factors, were found to be downregulated whereas p53 and VHL, which are tumor suppressors and angiogenesis inhibitors, were upregulated in the Rac1 siRNA transfected cells. Our results suggest that Rac1 may be involved in angiogenesis by controlling the expression of angiogenesis-related factors and provide a possible strategy for the treatment of tumor angiogenesis by targeting the Rac1 GTPase. (C) 2004 Elsevier Inc. All riahts reserved.