title: Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth.
abstract: OBJECTIVE
  Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma.
  
  
  METHODS
  Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors.
  
  
  RESULTS
  Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6-dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal-regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21 induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors.
  
  
  CONCLUSIONS
  Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease.
authors: Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University and T. Campanella Cancer Center, Catanzaro, Italy.
authors: Emanuela
authors: E
authors: Leone
authors: Eugenio
authors: E
authors: Morelli
authors: Maria T
authors: MT
authors: Di Martino
authors: Nicola
authors: N
authors: Amodio
authors: Umberto
authors: U
authors: Foresta
authors: Annamaria
authors: A
authors: Gullà
authors: Marco
authors: M
authors: Rossi
authors: Antonino
authors: A
authors: Neri
authors: Antonio
authors: A
authors: Giordano
authors: Nikhil C
authors: NC
authors: Munshi
authors: Kenneth C
authors: KC
authors: Anderson
authors: Pierosandro
authors: P
authors: Tagliaferri
authors: Pierfrancesco
authors: P
authors: Tassone
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016372:RNA, Antisense / Q000008:administration & dosage / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D017874:Immediate-Early Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D016372:RNA, Antisense; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020743:rhoB GTP-Binding Protein