title: Increased Expression of miR-23a Mediates a Loss of Expression in the RAF Kinase Inhibitor Protein RKIP.
abstract: RAF kinase inhibitor protein (RKIP) is a seminal regulator of intracellular signaling and exhibits both antimetastatic and antitumorigenic properties. Decreased expression of RKIP has been described in several human malignancies, including acute myelogenous leukemia (AML). As the mechanisms leading to RKIP loss in AML are still unclear, we aimed to analyze the potential involvement of miRNAs within this study. miRNA microarray and qPCR data of more than 400 AML patient specimens revealed correlation between decreased expression of RKIP and increased expression of miR-23a, a member of the miR-23a/27a/24-2 cluster. In functional experiments, overexpression of miR-23a decreased RKIP mRNA and protein expression, whereas miR-23a inhibition caused the opposite effect. By using an RKIP 3'-untranslated region luciferase reporter construct with and without mutation or deletion of the putative miR-23a-binding site, we could show that RKIP modulation by miR-23a is mediated via direct binding to this region. Importantly, miR-23a overexpression induced a significant increase of proliferation in hematopoietic cells. Simultaneous transfection of an RKIP expression construct lacking the miR-23a-binding sites reversed this phenotype, indicating that this effect is truly mediated via downregulation of RKIP. Finally, by analyzing more than 4,300 primary patient specimens via database retrieval from The Cancer Genome Atlas, we could highlight the importance of the miR-23a/RKIP axis in a broad range of human cancer entities. In conclusion, we have identified miR-23a as a negative regulator of RKIP expression in AML and have provided data that suggest the importance of our observation beyond this tumor entity. Cancer Res; 76(12); 3644-54. ©2016 AACR.
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hatzl
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Olivia
authors.initials: O
authors.lastname: Geiger
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Maja Kim
authors.initials: MK
authors.lastname: Kuepper
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Veronica
authors.initials: V
authors.lastname: Caraffini
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Till
authors.initials: T
authors.lastname: Seime
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Furlan
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Erika
authors.initials: E
authors.lastname: Nussbaumer
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria and Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Rotraud
authors.initials: R
authors.lastname: Wieser
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Institute for Diabetes and Cancer, Helmholtz Center Munich, Munich, Germany. University Hospital, Heidelberg University, Heidelberg, Germany. German Center for Diabetes Research (DZD), Neuherberg, Germany. Technical University of Munich, Munich, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Scheideler
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Nowek
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Mojca
authors.initials: M
authors.lastname: Jongen-Lavrencic
authors.affiliation: Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Quehenberger
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Albert
authors.initials: A
authors.lastname: Wölfler
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria. armin.zebisch@medunigraz.at.
authors.forename: Armin
authors.initials: A
authors.lastname: Zebisch
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology*; D049488:Phosphatidylethanolamine Binding Protein / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein