Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells
Menée in vitro sur des cellules humaines de cancer du pancréas, cette étude montre que la metformine, un médicament utilisé pour le traitement du diabète de type 2, peut inhiber la prolifération, la migration et l'invasion des cellules tumorales en modulant l'expression de gènes et de micro-ARNs dans les cellules souches cancéreuses
Pancreatic cancer (PC) 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 in order to improve overall survival of patients. Oral administration of metformin in diabetes mellitus (DM) patients has been reported to be associated with reduced risk of PC and that metformin has been reported to kill cancer stem cells (CSCs); 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, self-renewal capacity of cancer stem-like cells (CSC), and further assessed the expression of CSC marker genes and microRNAs (miRNAs) in human PC 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 PC cells. Metformin also decreased the expression of CSC markers, CD44, EpCAM, EZH2, Notch-1, Nanog and Oct4, and caused re-expression of miRNAs (let-7a, b, miR-26a, miR-101, and miR-200b, c) that are typically lost in PC and especially in pancreatospheres. We also found that re-expression of miR-26a by transfection led to decreased expression of EZH2 and EpCAM in PC cells. These results clearly suggest that the biological effects of metformin are mediated through re-expression of miRNAs and decreased expression of CSC-specific genes, suggesting