title: Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.
abstract: BACKGROUND
  ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known.
  
  
  RESULTS
  By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration.
  
  
  CONCLUSIONS
  Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer.
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. sara.tomaselli@opbg.net.
authors.forename: Sara
authors.initials: S
authors.lastname: Tomaselli
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. federica.galeano@opbg.net.
authors.forename: Federica
authors.initials: F
authors.lastname: Galeano
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, 69978, Israel. shaharal@post.tau.ac.il.
authors.forename: Shahar
authors.initials: S
authors.lastname: Alon
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. susanna.raho@opbg.net.
authors.forename: Susanna
authors.initials: S
authors.lastname: Raho
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, Rome, 00133, Italy. silvia.galardi@uniroma2.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Galardi
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. vassunta.polito@opbg.net.
authors.forename: Vinicia Assunta
authors.initials: VA
authors.lastname: Polito
authors.affiliation: Department of Genetics and Molecular Biology, Sapienza University of Rome, Via Dei Sardi 70, Rome, 00100, Italy. carlo.presutti@uniroma1.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Presutti
authors.affiliation: Department of Genetics and Molecular Biology, Sapienza University of Rome, Via Dei Sardi 70, Rome, 00100, Italy. sara.vincenti@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Vincenti
authors.affiliation: Raymond and Beverly Sackler School of Physics and Astronomy, Tel-Aviv University, Tel-Aviv, 69978, Israel. elieis@post.tau.ac.il.
authors.forename: Eli
authors.initials: E
authors.lastname: Eisenberg
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. franco.locatelli@opbg.net.|Department of Pediatric Science, Università di Pavia, Strada Nuova 65, Pavia, 27100, Italy. franco.locatelli@opbg.net.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Pediatric Oncohaematology, RNA Editing Laboratory, Bambino Gesù Children's Hospital IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy. angela.gallo@opbg.net.
authors.forename: Angela
authors.initials: A
authors.lastname: Gallo
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism*; D000293:Adolescent; D000818:Animals; D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D017393:RNA Editing / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase