HIF-1α RNA干扰与内皮抑素基因联合对肺癌裸鼠移植瘤的生长抑制作用

Inhibitory Effects of the Combination of RNA Interference on HIF-1α and Endostatin in the Growth of Lung Tumor

目的探讨缺氧诱导因子-1α(hypoxia inducible factor 1 alpha,HIF-1α)RNA干扰与内皮抑素(endostatin,ET)基因联合对人肺癌裸鼠移植瘤的生长抑制作用。方法 SPCA1/HIF-1α(-)人肺癌细胞的裸鼠,给予脂质体-内皮抑素基因转染,观察转然瘤组织7、14、21天的HIF-1α、内皮生长因子(vascular endothelial growth factor,VEGF)蛋白表达及微血管生成数量。结果 HIF-1α RNA干扰明显降低瘤组织内VEGF蛋白表达;HIF-1α RNA干扰、ET及联合治疗均显著抑制肿瘤微血管生成;至接种后21天,HIF-1α RNA干扰ET联合组肿瘤体积为(312.7±78.6)mm3,抑瘤率为64.3%,与对照组比(P<0.01)显著高于HIF-1α RNA干扰组(39.8%)和单用内皮抑素组(43.1%)。结论 HIF-1α RNA干扰与ET基因联合应用,显著抑制人肺癌裸鼠移植瘤生长。

Objective To explore the co-operative inhibitory effect of combining small interfering RNA（siRNA）targeted to hypoxia-inducible factor-1α（HIF-1α）with endostatin gene transfer on tumor growth.Methods SPCA1/HIF-1α（-）cells were transplanted into nude mice,then tumors were injected with liposome-endostatin gene complexes for 7,14 and 21 days after the injection of the tumor cells.The vascular endothelial growth factor（VEGF）and HIF-1α expression,microvessel density（MVD）and tumor growth were observed.Results The expression of HIF-1α and VEGF reduced specifically in response to siRNA targeted to HIF-1α.Sections from tumors treated with siRNA targeted to HIF-1α,endostatin or a combination of them showed a marked decrease in MVDs compared with those observed in the control group.The combination of local endostatin gene therapy with siRNA targeted to HIF-1α inhibited the growth of human lung cancer SPCA-1 xenografts significantly,whose size was（312.7±78.6）mm3 and inhibition rate of tumor was 64.3% 21 days later.Using endostatin or small interfering RNA targeted to HIF-1α alone could also inhibit the growth of lung cancer in vitro,but their inhibition effects were weaker than those from their combination,whose inhibition rates 21 days later were 39.8% and 43.1%,respectively.Conclusions Combining siRNA targeted to HIF-1α with endostatin gene transfer can inhibit the tumor growth markedly.