Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells

Aims: To investigate the effect of metformin on the expression profiles of microRNAs in human pancreatic cancer cells. Methods: MicroRNAs real-time PCR Array was applied to investigate differentially expressed miRNAs in Sw1990 cells treated with or without metformin. Stem-loop real time RT-PCR was used to confirm the results of the array assay in Sw1990 and Panc-1 cells. The effects of miR-26a on cell growth, apoptosis, invasion and migration abilities were respectively examined by CCK8 assay, Apoptosis assay, Matrigel invasion and migration assay. HMGA1 was proved to be a target of miR-26a by Luciferase reporter assay, Real-time PCR and Western-blotting. Results: Nine miRNAs were significantly up-regulated in metformin treated cells. Metformin up-regulated the expression of miR-26a, miR-192 and let-7c in a dose-dependent manner. Forced expression of miR-26a significantly inhibited cell proliferation, invasion, migration and increased cell apoptosis, whereas knockdown of miR-26a obtained the opposite effect. Furthermore, we demonstrated that HMGA1, an oncogene, is a direct target of miR-26a. Nude mice xenograft models confirmed that metformin up-regulated the level of miR-26a and surpressed the expression of HMGA1 in vivo. Conclusion: These observations suggested that modulation of miRNA expression may be an important mechanism underlying the biological effects of metformin. (C) 2011 Elsevier Ireland Ltd. All rights reserved.