title: Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication.
abstract: MicroRNA have been demonstrated to be deregulated in multiple myeloma. We have previously reported that miR-214 is down-regulated in multiple myeloma compared to in normal plasma cells. The functional role of miR-214 in myeloma pathogenesis was explored by transfecting myeloma cell lines with synthetic microRNA followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this microRNA, gene expression profiling of the H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR-214 directly down-regulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-untranslated regions. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent up-regulation of CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, MiR-214 functions as a tumor suppressor in myeloma by positive regulation of p53 and inhibition of DNA replication.
authors.affiliation: Servicio de Hematología, Hospital Universitario, IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.
authors.forename: Irena
authors.initials: I
authors.lastname: Misiewicz-Krzeminska
authors.forename: María E
authors.initials: ME
authors.lastname: Sarasquete
authors.forename: Dalia
authors.initials: D
authors.lastname: Quwaider
authors.forename: Patryk
authors.initials: P
authors.lastname: Krzeminski
authors.forename: Fany V
authors.initials: FV
authors.lastname: Ticona
authors.forename: Teresa
authors.initials: T
authors.lastname: Paíno
authors.forename: Manuel
authors.initials: M
authors.lastname: Delgado
authors.forename: Andreia
authors.initials: A
authors.lastname: Aires
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Ocio
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.forename: Norma C
authors.initials: NC
authors.lastname: Gutiérrez
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004261:DNA Replication; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C491640:ASF1B protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex