Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Mol Cancer Ther. 2012 Mar;11(3):549-60. doi: 10.1158/1535-7163.MCT-11-0594. Epub 2012 Jan 5.
Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G(0)-G(1)in vitro and in vivo. This blockade was accompanied by a strong decrease of G(1) cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo.
最近的研究表明，二甲双胍作为双胍类家族的一种常用口服降血糖药物，可能降低癌症风险并改善预后，但二甲双胍影响包括胃癌在内的各种癌症的机制尚不清楚。本研究旨在评估二甲双胍在体外和体内对人胃癌细胞增殖的影响，并研究与二甲双胍抗肿瘤作用相关的 microRNAs（miRNA）。我们使用 MKN1、MKN45 和 MKN74 人胃癌细胞系研究二甲双胍对人胃癌细胞的影响。用或不用二甲双胍处理荷有人胃癌细胞系移植瘤的裸鼠。4 周后记录肿瘤生长情况，并测定细胞周期相关蛋白的表达。此外，我们还使用 miRNA 阵列 tip 来探讨体外和体内荷有人胃癌细胞系移植瘤的 MKN74 细胞中 miRNA 的差异。二甲双胍抑制 MKN1、MKN45 和 MKN74 的体外增殖。二甲双胍在体外和体内将细胞周期阻滞在 G0-G1 期。这种阻滞伴随着 G1 周期蛋白，特别是 cyclin D1、细胞周期蛋白依赖性激酶（Cdk）4、Cdk6 的强烈减少和视网膜母细胞瘤蛋白（Rb）磷酸化的减少。此外，二甲双胍还降低了体外和体内表皮生长因子受体和胰岛素样生长因子-1 受体的磷酸化。miRNA 的表达在体外和体内用二甲双胍处理后明显改变。二甲双胍改变的各种 miRNA 也可能有助于体外和体内的肿瘤生长。
