6533b822fe1ef96bd127ce75

RESEARCH PRODUCT

miR-22 suppresses DNA ligase III addiction in multiple myeloma

Pierfrancesco TassonePierfrancesco TassoneEmanuela AltomareNicola AmodioLorenza MalteseFrancesca SciontiValeria ZuccalàMariamena ArbitrioEugenio MorelliMarco RossiMartina MontesanoDaniele CaraccioloMaria Eugenia Gallo CantafioCirino BottaAntonino NeriPierosandro TagliaferriDaniela TalaricoMaria Teresa Di MartinoKatia Todoerti

subject

0301 basic medicineGenome instabilityCancer ResearchmiR-22 LIG3DNA repairDNA damageDNA repairApoptosisLIG3ArticleDNA Ligase ATP03 medical and health sciences0302 clinical medicinemicroRNABiomarkers TumorTumor Cells CulturedHumansPoly-ADP-Ribose Binding ProteinsCell ProliferationmiRNAchemistry.chemical_classificationRegulation of gene expressionGene knockdownDNA ligaseLeukemiamicroRNAChemistryHematologyPrognosisXenograft Model Antitumor AssaysGene Expression Regulation Neoplasticmultiple myelomaMicroRNAs030104 developmental biologyOncology030220 oncology & carcinogenesisCancer researchpharmacologyDNA Damage

description

Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.

yearjournalcountryeditionlanguage
2019-01-01Leukemia
https://doi.org/10.1038/s41375-018-0238-2