title: miR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis.
abstract: Glucocorticoid (GC) hormones are an important ingredient of leukemia therapy since they are potent inducers of lymphoid cell apoptosis. However, the development of GC resistance remains an obstacle in GC-based treatment. In the present investigation we found that miR-103 is upregulated in GC-sensitive leukemia cells treated by the hormone. Transfection of GC resistant cells with miR-103 sensitized them to GC induced apoptosis (GCIA), while miR-103 sponging of GC sensitive cells rendered them partially resistant. miR-103 reduced the expression of cyclin dependent kinase (CDK2) and its cyclin E1 target, thereby leading to inhibition of cellular proliferation. miR-103 is encoded within the fifth intron of PANK3 gene. We demonstrate that the GC receptor (GR) upregulates miR-103 by direct interaction with GC response element (GRE) in the PANK3 enhancer. Consequently, miR-103 targets the c-Myc activators c-Myb and DVL1, thereby reducing c-Myc expression. Since c-Myc is a transcription factor of the miR-17~92a poly-cistron, all six miRNAs of the latter are also downregulated. Of these, miR-18a and miR-20a are involved in GCIA, as they target GR and BIM, respectively. Consequently, GR and BIM expression are elevated, thus advancing GCIA. Altogether, this study highlights miR-103 as a useful prognostic biomarker and drug for leukemia management in the future.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Kfir-Erenfeld
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Haggiag
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Biton
authors.affiliation: Pediatric Hemato-Oncology and Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Assayag-Asherie
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Yefenof
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D000072261:Dishevelled Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns / Q000235:genetics; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D005938:Glucocorticoids; C544749:MIRN103 microRNA, human; C581632:MIRN18 microRNA, human; C534451:MIRN20a microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D011965:Receptors, Glucocorticoid; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: apoptosis; glucocorticoid; leukemia; miR-103; proliferation