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二甲双胍对ALDH+胃癌干细胞的抑制作用及其机制
作者:王一 向勇平 刘丹丹 刘理金 姜伟 李锦毅 
单位:100039 北京 锦州医科大学武警总医院研究生培养基地(王一、向勇平、刘丹丹、刘理金) 100039 北京 武警总医院临床教研室(姜伟、李锦毅) 100039 北京 灾害救援医学北京市重点实验室(向勇平、刘理金) 
关键词:肿瘤干细胞 乙醛脱氢酶 二甲双胍 Oct4 Sox2 AKT 
分类号:R735
出版年,卷(期):页码:2018,43(1):7-11
摘要:
[摘要] 目的 探讨二甲双胍(Met)对乙醛脱氢酶(ALDH)阳性胃癌干细胞的抑制作用及其可能机制。方法 选择人胃癌细胞系MKN45作为亲本细胞,采用流式细胞仪分选出ALDH+ALDH细胞,进行自我更新能力、分化能力、裸鼠移植瘤实验,鉴定其是否为胃癌干细胞及是否具备肿瘤干细胞特性。实验设置1mmol/L Met组、5mmol/L Met组和MKN45细胞组,分别作用48h后,检测各组ALDH+细胞的比例;RT-PCR实验检测各组Oct4Sox2AKT基因表达量的变化。结果 细胞鉴定实验结果显示,ALDH+细胞的自我更新能力、分化能力、致瘤能力均高于ALDH细胞,表明ALDH+细胞具有肿瘤干细胞特性。实验结果显示,MKN45细胞组、1mmol/L Met组、5mmol/L MetALDH+细胞比例分别为36.5%±5.4%15.6%±1.9%7.6%±1.6%,三组差异有统计学意义(P0.01)RT-PCR结果显示,Met处理后Sox2AKT基因的表达量均下降,且随Met浓度升高下降更为明显;Oct4基因在1mmol/L Met组的表达量高于MKN45细胞组,5mmol/L Met组的表达量低于MKN45细胞组。结论 Met能抑制ALDH+胃癌干细胞生长,抑制AKT基因的表达,可作为临床治疗胃癌的靶点药物。

 

[Abstract] Objective To investigate the inhibitory effect of metformin (Met) on ALDH positive (ALDH+) gastric cancer stem cells and its mechanism. Methods ALDH+ and ALDH cells were isolated from human gastric cancer cell line MKN45 by flow cytometry. The characteristics of cancer stem cells of ALDH+ cells was verified by self-renewing ability, differentiation capacity experiments and tumorigenicity in nude mice. 1mmol/L Met group, 5mmol/L Met group and control group (MKN45 cell) were set up. After being acted on MKN45 cell for 48h, the proportion of ALDH+ cells in each group was detected by flow cytometry. RT-PCR test was performed to detect the expression of Oct4, Sox2 and AKT genes in the 3 groups. Results The cell identification showed that the self-renewal ability, differentiation capacity and tumorigenicity of ALDH+ cells were higher than that of ALDH cells. Drug experiments indicated that the proportion of ALDH+ cells in control group, 1mmol/L Met group and 5mmol/L Met group were 36.5%±5.4%, 15.6%±1.9% and 7.6%±1.6%, respectively. The difference between the 3 groups was statistically significant (P<0.01). RT-PCR revealed that the expressions of Sox2 and AKT genes decreased after Met treatment, and decreased with the increase of Met concentration. The expression of Oct4 gene was higher in 1 mmol/L Met group than in control group, and was lower in 5mmol/L Met group than in control group. Conclusion Met may inhibit the growth of ALDH+ gastric cancer stem cells and the expression of AKT gene, and can be used as a target drug for the clinical treatment of gastric cancer.

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