二甲双胍通过抑制PI3K/Akt通路诱导杀伤肝癌干细胞的机制研究  

Metformin-induced killing of liver initiating cells by inhibiting the PI3K/Akt pathway

作　　者：詹鹏 郭放 郑振东 刘兆喆 ZHAN Peng;GUO Fang;ZHENG Zhen-dong;LIU Zhao-zhe(Department of Oncology,General Hospital of the Northern Theater Command,Shenyang 110016,China)

机构地区：[1]北部战区总医院肿瘤科,辽宁沈阳110016

出　　处：《解剖科学进展》2024年第2期117-120,共4页Progress of Anatomical Sciences

基　　金：辽宁省自然科学基金(2019-MS-351)。

摘　　要：目的探讨二甲双胍对肝癌细胞自我更新作用的影响及潜在机制。方法成球实验和体外细胞培养法检测二甲双胍对体外肝癌细胞自我更新作用的影响。应用索拉非尼处理细胞后,对比二甲双胍和DMSO两组细胞的凋亡情况。二甲双胍处理SMMC-7721细胞后,采用Real-time PCR法检测细胞CD90、CD133和Sox2 mRNA的表达水平,Western blot检测细胞p-Akt和p-mTOR蛋白的表达。应用动物模型探讨二甲双胍对SMMC-7721注射NOD/SCID小鼠的影响。结果二甲双胍可降低肝癌细胞中肿瘤干细胞的比例。索拉非尼处理细胞后,SMMC-7721-二甲双胍组细胞凋亡的比例显著高于SMMC-771-DMSO组。二甲双胍处理SMMC-7721细胞后,CD90、CD133和Sox2表达显著下调。二甲双胍明显减弱肝癌细胞的成球能力。此外,在二甲双胍处理的SMMC-7721细胞中PI3K/Akt通路下调,阻断PI3K/Akt通路可降低二甲双胍对细胞的抑制能力。结论二甲双胍通过PI3K/Akt信号通路诱导杀伤肝细胞癌中的肿瘤干细胞,有望成为一种潜在的肝细胞癌治疗药物。Objective To investigate the effect of metformin on self-renewal of hepatocellular carcinoma cells and its potential mechanism.Methods The effect of metformin on self-renewal of hepatocellular carcinoma cells in vitro was examined by pellet forming experiment and cell culture in vitro.The apoptosis of cells treated with sorafenib was compared between metformin and DMSO.After SMMC-7721 cells were treated with metformin,the mRNA expression levels of CD90,CD133 and Sox2 were detected by Real-time PCR,and the protein expressions of p-Akt and p-mTOR were detected by Western blot.The effects of metformin on NOD/SCID mice injected with SMMC-7721 were studied in animal model.Results Metformin reduced the proportion of tumor stem cells in liver cancer cells.After sorafenib treatment,the apoptosis rate of SMMC-7721-metformin group was significantly higher than SMMC-771-DMSO group.SMMC-7721 cells were treated with metformin,and the expressions of CD90,CD133 and Sox2 were significantly down-regulated.Metformin significantly reduced the pelletizing ability of hepatocellular carcinoma cells.In addition,the PI3K/Akt pathway was down-regulated in metformin-treated SMMC-7721 cells,and blocking the PI3K/Akt pathway reduced the inhibitory ability of metformin on the cells.Conclusion Metformin plays an important role in HCC tumor-initiating cells through PI3K/Akt signaling and may be a promising therapeutic drug for HCC patients.

关 键 词：二甲双胍 肝细胞癌 肿瘤干细胞 PI3K/AKT通路 

分 类 号：R735.7[医药卫生—肿瘤]