title: Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.
abstract: 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.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 740 Hudson Webber Cancer Research Center, 4100 John R Street, Detroit, MI 48201, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.forename: Sanila H
authors.initials: SH
authors.lastname: Sarkar
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Shivam
authors.initials: S
authors.lastname: Thakur
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D035683:MicroRNAs; D012333:RNA, Messenger; D014157:Transcription Factors; D003841:Deoxycytidine; D008687:Metformin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000093542:Gemcitabine
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