雷帕霉素对人肝癌裸鼠皮下移植瘤生长的抑制作用

Inhibitory effect of rapamycin on tumor growth in nude mice bearing subcutaneous xenograft human hepatoceilular carcinoma

目的探讨雷帕霉素对人肝癌裸鼠皮下移植瘤生长的影响及机制。方法建立人肝癌裸鼠皮下移植瘤模型24只,随机分为对照组、RAPA 小剂量组(每日1 mg/kg 体重)、RAPA 大剂量组(每日5 mg/kg 体重)。用药4周后观察肿瘤体积和重量、肿瘤组织切片行透射电镜检查、荧光定量聚合酶链反应(PCR)法检测肿瘤的血管内皮生长因子(VEGF)、基质金属蛋白酶2(MMP-2)mRNA 的表达,酶联免疫吸附试验(ELISA)法测定裸鼠血 VEGF、MMP-2浓度。结果与对照组比较,雷帕霉素小剂量组和大剂量组均能抑制肿瘤生长[(0.42±0.17)cm^3和(0.38±0.21)cm^3比(0.78±0.25)cm^3,P<0.05];VEGF mRNA、MMP-2 mRNA 的转录和翻译显著减少(P<0.01)。结论雷帕霉素可以通过抑制肝癌细胞 VEGF 和 MMP-2的 mRNA 转录和蛋白表达,抑制肿瘤生长,但不呈剂量依赖性。

Objective To study the effect of Rapamycin on tumor growth in nude mice bearing subcutaneous xenograft human hepatocellular carcinoma （HCC） and the mechanism. Methods Twentyfour nude mice bearing subcutaneous xenograft HCC were randomly divided into 3 group： the control group,the low dose group and the high dose group. The effect of Rapamycin was evaluated after 4 weeks, including the tumor volume and weight. The expression of VEGF mRNA and MMP-2 mRNA was detected by fluorescent quantitative polymerase chain reaction （FQ-PCR）. The serum concentration of VEGF and MMP-2 in nude mice was determined by enzyme-linded immunosorbent assay （ELISA）. Results Tumor weight and volume were significantly decreased in both low dose Ramamycin and high dose Ramamycin groups as compared with control group [ （0.42 ± 0.17 ） cm^3 （0.38 ± 0.21 ） cm^3 vs （0.78 ±0.25 ） cm^3, P 〈 0.05 ]. The expression of VEGF mRNA and MMP-2 mRNA and their protein products were down-regulated significantly in both Rapamycin groups as compared with control group （P 〈0.01 ）. Conclusion Rapamycin inhibits tumor growth in nude mice by antiangiogenesis and downregulating the MMP-2 expression. The anti-tumor effcet of Rapamycin dose not depend on the dosage.