title: MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis.
abstract: 1,25-Dihydroxyvitamin D(3) (1,25D) used to treat human acute myeloid leukemia (AML) cells induces features of normal monocytes, but the mechanisms underlying this response are not fully understood. We hypothesized that one or more microRNAs (miRNA) known to control mouse hematopoiesis and lineage commitment might contribute to the ability of 1,25D to control the malignant phenotype. Here we report that 1,25D markedly induces expression of miR-32 in human myeloid leukemia cells, in which it targets the 3'-untranslated region of the mRNA encoding the proapoptotic factor Bim to reduce its expression. RNAi-mediated suppression of the miRNA-processing enzymes Drosha and Dicer increased Bim levels, in support of the concept that Bim is under miRNA control in AML cells. Antisense-mediated suppression of miR-32 was sufficient to upregulate Bim expression in AML cells. Conversely, ectopic expression of miR-32 downregulated Bim expression and increased the differentiation response to 1,25D treatment in a manner that was associated with increased cell survival. The positive effects of miR-32 on cell survival were confirmed by evidence of increased cell death in AML cells preexposed to antisense miR-32 before treatment with arabinocytosine, a chemotherapeutic drug used to treat human AML. Together, our findings indicate that miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis. Thus, agents which can inhibit miR-32 expression may offer clinical utility by enhancing therapeutic efficacy in human AML.
authors.affiliation: Department of Pathology and Laboratory Medicine, UMD-New Jersey Medical School, Newark, New Jersey 07101, USA.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Gocek
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002454:Cell Differentiation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020320:Oligoribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C568529:MIRN32 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D020320:Oligoribonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D003561:Cytarabine; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D