title: miR-150 exerts antileukemia activity in vitro and in vivo through regulating genes in multiple pathways.
abstract: MicroRNAs, a class of small noncoding RNAs, have been implicated to regulate gene expression in virtually all important biological processes. Although accumulating evidence demonstrates that miR-150, an important regulator in hematopoiesis, is deregulated in various types of hematopoietic malignancies, the precise mechanisms of miR-150 action are largely unknown. In this study, we found that miR-150 is downregulated in samples from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia, and normalized after patients achieved complete remission. Restoration of miR-150 markedly inhibited growth and induced apoptosis of leukemia cells, and reduced tumorigenicity in a xenograft leukemia murine model. Microarray analysis identified multiple novel targets of miR-150, which were validated by quantitative real-time PCR and luciferase reporter assay. Gene ontology and pathway analysis illustrated potential roles of these targets in small-molecule metabolism, transcriptional regulation, RNA metabolism, proteoglycan synthesis in cancer, mTOR signaling pathway, or Wnt signaling pathway. Interestingly, knockdown one of four miR-150 targets (EIF4B, FOXO4B, PRKCA, and TET3) showed an antileukemia activity similar to that of miR-150 restoration. Collectively, our study demonstrates that miR-150 functions as a tumor suppressor through multiple mechanisms in human leukemia and provides a rationale for utilizing miR-150 as a novel therapeutic agent for leukemia treatment.
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Zhi Hong
authors.initials: ZH
authors.lastname: Fang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Si Li
authors.initials: SL
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Jin Tao
authors.initials: JT
authors.lastname: Zhao
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Zhi Juan
authors.initials: ZJ
authors.lastname: Lin
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Lin Yan
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Si Ting
authors.initials: ST
authors.lastname: Xie
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C533097:MIR150, human