title: MiRNA-21 mediates the antiangiogenic activity of metformin through targeting PTEN and SMAD7 expression and PI3K/AKT pathway.
abstract: Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays. In this study, miR-21 was strikingly downregulated by metformin in a time- and dose-dependent manner. miR-21 directly targeted the 3'-UTR of PTEN and SMAD7, and negatively regulated their expression. Overexpression of miR-21 abrogated the metformin-mediated inhibition of endothelial cells proliferation, migration, tubule formation and the TGF-β-induced AKT, SMAD- and ERK-dependent phosphorylations, and conversely, down-regulation of miR-21 aggravated metformin's action and revealed significant promotion effects. Our study broadens our understanding of the regulatory mechanism of miR-21 mediating metformin-induced anti-angiogenic effects, providing important implications regarding the design of novel miRNA-based therapeutic strategies against angiogenesis.
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Luo
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Tan
authors.affiliation: Affiliated TCM Hospital of Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Mu
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Meiping
authors.initials: M
authors.lastname: Ren
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Drug Discovery Reseach Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.|Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wan
mesh_terms: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008687:Metformin; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051906:Smad7 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D020533:Angiogenesis Inhibitors; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D008687:Metformin; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human