title: Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia.
abstract: Deregulation of microRNAs' expression frequently occurs in acute myeloid leukemia (AML). Lower miR-181a expression is associated with worse outcomes, but the exact mechanisms by which miR-181a mediates this effect remain elusive. Aberrant activation of the RAS pathway contributes to myeloid leukemogenesis. Here, we report that miR-181a directly binds to 3'-untranslated regions (UTRs); downregulates KRAS, NRAS and MAPK1; and decreases AML growth. The delivery of miR-181a mimics to target AML cells using transferrin-targeting lipopolyplex nanoparticles (NP) increased mature miR-181a; downregulated KRAS, NRAS and MAPK1; and resulted in decreased phosphorylation of the downstream RAS effectors. NP-mediated upregulation of miR-181a led to reduced proliferation, impaired colony formation and increased sensitivity to chemotherapy. Ectopic expression of KRAS, NRAS and MAPK1 attenuated the anti-leukemic activity of miR-181a mimics, thereby validating the relevance of the deregulated miR-181a-RAS network in AML. Finally, treatment with miR-181a-NP in a murine AML model resulted in longer survival compared to mice treated with scramble-NP control. These data support that targeting the RAS-MAPK-pathway by miR-181a mimics represents a novel promising therapeutic approach for AML and possibly for other RAS-driven cancers.
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Xiaomeng
authors: X
authors: Huang
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Sebastian
authors: S
authors: Schwind
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Ramasamy
authors: R
authors: Santhanam
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Ann-Kathrin
authors: AK
authors: Eisfeld
authors: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Chi-Ling
authors: CL
authors: Chiang
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Malori
authors: M
authors: Lankenau
authors: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.|William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
authors: Bo
authors: B
authors: Yu
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Pia
authors: P
authors: Hoellerbauer
authors: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors: Yan
authors: Y
authors: Jin
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Somayeh S
authors: SS
authors: Tarighat
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Jihane
authors: J
authors: Khalife
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Alison
authors: A
authors: Walker
authors: Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors: Danilo
authors: D
authors: Perrotti
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Clara D
authors: CD
authors: Bloomfield
authors: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Hongyan
authors: H
authors: Wang
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.|Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors: Robert J
authors: RJ
authors: Lee
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.|William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.
authors: Ly James
authors: LJ
authors: Lee
authors: Molecular Cellular and Developmental Biology, The Ohio State University, Columbus, OH, USA.|Gehr Family Leukemia Center, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Guido
authors: G
authors: Marcucci
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D053758:Nanoparticles; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; C117307:KRAS protein, human; C540193:MIrn181 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RAS; acute myeloid leukemia; miR-181a; microRNA; nanoparticles