二甲双胍联合奥沙利铂对肺癌裸鼠移植瘤 VEGF-C、VEGFR-3、CD44 v6和β-catenin 表达的影响

摘要

目的：探讨二甲双胍联合奥沙利铂对肺癌裸鼠移植瘤血管内皮生长因子-C（ VEGF-C）、血管内皮生长因子受体-3（VEGFR-3）、CD44变异体蛋白6（CD44v6）和β-链蛋白（β-catenin）分子表达水平的影响。方法建立肺癌裸鼠移植瘤模型，将裸鼠随机分为二甲双胍组、奥沙利铂组、联合用药组及对照组，每组分别给予二甲双胍、奥沙利铂、二甲双胍＋奥沙利铂及灭菌蒸馏水等干预，42 d后处死动物，留取肿瘤组织，分别采用免疫组织化学法及实时荧光定量PCR法检测肿瘤组织中VEGF-C、VEGFR-3、CD44v6和β-catenin蛋白及mRNA的表达。结果二甲双胍组、奥沙利铂组和联合用药组的抑瘤率分别为28．97％、34．37％和50．27％。与对照组相比，奥沙利铂组、联合用药组VEGF-C、VEGFR-3、CD44v6和β-catenin蛋白及mRNA表达水平均降低（P均＜0．05）；与二甲双胍组、奥沙利铂组比较，联合用药组VEGF-C、VEGFR-3、CD44v6和β-catenin 蛋白及mRNA表达水平均降低（P 均＜0．05）， VEGF-C、VEGFR-3、CD44v6和 β-catenin 蛋白组间比较有统计学差异（ F 值分别为79．281、151．275、171．294、164．149，P均＜0．01）；VEGF-C、VEGFR-3、CD44v6和β-catenin mRNA组间比较差异均有统计学意义（F值分别为78．897、81．029、64．100、83．892，P均＜0．01）。结论奥沙利铂及二甲双胍均可抑制VEGF-C、VEGFR-3、CD44v6和β-catenin的表达，联合应用抑制效果更强。%Objective To investigate the effects of metformin combined with oxaliplatin on the expression levels of vascular endothelial growth factor-C (VEGF-C), vascular endothelial growth factor receptor-3 (VEGFR-3), CD44v6 andβ-catenin of lung cancer xenograft in nude mice .Methods We established human lung cancer xenograft models in the nude mice.The nude mice were randomly divided into metformin-treated, oxaliplatin-treated, metformin combined with ox-aliplatin-treated and untreated control groups .Forty-two days after administration , all the nude mice were sacrificed and tumor tissues were sampled.The protein and mRNA expression of VEGF-C, VEGFR-3, CD44v6 and β-catenin in the tumor tissues was detected by immumohistochemical method and florescent real-time quantitative PCR , repectively .Results The respective tumor inhibition rates of metformin-treated group , oxaliplatin-treated group and metformin combined with oxaliplatin-treated group were 28.97%, 34.37%and 50.27%.The expression levels of VEGF-C,VEGFR-3, CD44v6 andβ-catenin protein and mRNA in the oxaliplatin-treated and metformin combined with oxaliplatin-treated groups were lower than those in the control group, respectively (all P<0.05).Compared with the metformin-treated group and oxaliplatin-treated group, the expression levels of VEGF-C,VEGFR-3, CD44v6 and β-catenin protein and mRNA of the metformin combined with oxaliplatin-treated group were lower, respectively (all P<0.05).F values about comparison of VEGF-C, VEGFR-3, CD44v6 andβ-catenin proteins within four groups were 79.281, 151.275, 171.294 and 164.149, respectively (all P<0.01);F values about comparison of VEGF-C,VEGFR-3, CD44v6 andβ-catenin mRNA within four groups were 78.897, 81.029, 64.100 and 83.892, respectively (all P<0.01).Conclusions Using oxaliplatin or metformin can in-hibit the expression of VEGF-C,VEGFR-3, CD44v6 and β-catenin.The combination of metformin and oxaliplatin can en-hance the anti-tumor efficacy .