二甲双胍通过IGF-1RSTAT3信号通路抑制前列腺癌生长的实验研究

Experimental study on metformin's inhibition of prostate cancer growth via IGF-1R STAT3 signaling pathway

目的探讨二甲双胍对前列腺癌细胞的生物学功能影响及其机制。方法使用4～6周龄的SPF级BALB/c裸鼠,注射DU145细胞系建立前列腺癌小鼠模型。将小鼠随机分为对照组、二甲双胍组、PPP组,每组6只。对照组给予100μl生理盐水,二甲双胍组给予50μl生理盐水+50μl二甲双胍(250 mg/kg),PPP组给予50μl生理盐水+50μl 0.1μM鬼柏苦(PPP),每日瘤内注射1次。注射3 w后,处死小鼠,检测小鼠肿瘤重量,分析二甲双胍对前列腺癌生长的影响作用;qRT-PCR、WB法测定肿瘤组织中IGF-1R、STAT3的mRNA与蛋白的表达水平,ELISA法检测小鼠血清中IL-6和TNF-α的含量。结果与对照组相比,二甲双胍组、PPP组的肿瘤大小、体积显著降低。与对照组相比,二甲双胍组IGF-1R、STAT3的mRNA与蛋白表达显著减少,血清IL-6的含量显著减少;PPP组的IGF-1R mRNA表达显著低于二甲双胍组,二甲双胍组STAT3 mRNA表达显著低于PPP组。结论二甲双胍可能通过下调IGF1R/STAT3信号通路,抑制小鼠前列腺癌的生长。

Objective To explore the biological thnction of metformin on prostate cancer cells and its mechanism. Methods SPF BALB/c nude mice aged four to six weeks were injected with DUI45 cell line to establish prostate cancer model in mice. The mice were randomly divided into a control group, a metformin group and a PPP group （n=6, respectively）. The control group was injected with 100 μl nonnal saline, the metformin group was injected with 50 μl normal saline ＋ 50 μl metformin （250 mg/kg）, and the PPP group was injected with 50 μl nonnal saline ＋ 50 μl 0.1 μM picropodophyllin （PPP）, which was injected intratumorally once a day. After three weeks of injection, the mice were killed to measure the tumor weight and analyze the impacts of metformin on prostate cancer growth; the expression levels of the mRNA and protein in IGF-1R and STAT3 in tumor tissue were detected by qRT-PCR and WB. The contents of IL-6 and TNF-α in mouse serum were detected by ELISA. Results The tumor size and volume in the metformin group and the PPP group were significantly smaller than those in the control group. The expression levels of the mRNA and protein in IGF-1R and STAT3 in the metformin group were significantly lower and the contents of serum IL-6 were much less than those in the control group; the expression levels of IGF-IR mRNA in the PPP group were significantly lower than those in the metformin group, and the expression levels of STAT3 mRNA in the metformin group were much lower than those in the PPP group. Conclusion Metformin may inhibit the growth of prostate cancer by downregulating IGF1R/STAT3 signaling pathway.