Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.
Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.
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DOI：
10.1158/1940-6207.capr-11-0299
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Sarkar FH
中科院分区：
文献类型：
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作者：
Bao B;Wang Z;Ali S;Ahmad A;Azmi AS;Sarkar SH;Banerjee S;Kong D;Li Y;Thakur S;Sarkar FH
胰腺癌是美国癌症相关死亡的第四大原因，部分原因是对传统疗法的内在(从头)和外在(后天)抵抗，这表明需要创新的治疗策略来克服治疗阻力，以提高患者的总体存活率。据报道，糖尿病患者口服二甲双胍可降低患胰腺癌的风险，并可杀死肿瘤干细胞；然而，确切的分子机制(S)尚未完全阐明。在本研究中，我们检测了二甲双胍对细胞增殖、细胞迁移和侵袭以及CSC自我更新能力的影响，并进一步检测了CSC标志基因和microRNAs(MiRNA)在人胰腺癌细胞中的表达。我们发现，在吉西他滨敏感和耐药的胰腺癌细胞中，二甲双胍显著降低了细胞存活率、克隆形成能力、伤口愈合能力、球体形成能力(胰球体)，并增加了胰球体的解体。二甲双胍还降低CSC标记物CD44、EpCAM、EZH2、Notch-1、Nanog和Oct4的表达，并导致在胰腺癌尤其是胰球部典型缺失的miRNAs(let-7a、let-7b、miR-26a、miR-101、miR-200b和miR-200c)的重新表达。我们还发现，通过转染miR-26a重新表达会导致EZH2和EpCAM在胰腺癌细胞中的表达降低。这些结果清楚地表明，二甲双胍的生物学作用是通过重新表达miRNAs和降低CSC特异性基因的表达来实现的，这表明二甲双胍可能有助于克服胰腺癌细胞的治疗耐药。
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, which is, in part, due to intrinsic (de novo) and extrinsic (acquired) resistance to conventional therapeutics, suggesting that innovative treatment strategies are required for overcoming therapeutic resistance to improve overall survival of patients. Oral administration of metformin in patients with diabetes mellitus has been reported to be associated with reduced risk of pancreatic cancer and that metformin has been reported to kill cancer stem cells (CSC); however, the exact molecular mechanism(s) has not been fully elucidated. In the current study, we examined the effect of metformin on cell proliferation, cell migration and invasion, and self-renewal capacity of CSCs and further assessed the expression of CSC marker genes and microRNAs (miRNA) in human pancreatic cancer cells. We found that metformin significantly decreased cell survival, clonogenicity, wound-healing capacity, sphere-forming capacity (pancreatospheres), and increased disintegration of pancreatospheres in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. Metformin also decreased the expression of CSC markers, CD44, EpCAM, EZH2, Notch-1, Nanog and Oct4, and caused reexpression of miRNAs (let-7a, let-7b, miR-26a, miR-101, miR-200b, and miR-200c) that are typically lost in pancreatic cancer and especially in pancreatospheres. We also found that reexpression of miR-26a by transfection led to decreased expression of EZH2 and EpCAM in pancreatic cancer cells. These results clearly suggest that the biologic effects of metformin are mediated through reexpression of miRNAs and decreased expression of CSC-specific genes, suggesting that metformin could be useful for overcoming therapeutic resistance of pancreatic cancer cells.