title: MiR-221/222 target the DNA methyltransferase MGMT in glioma cells.
abstract: Glioblastoma multiforme (GBM) is one of the most deadly types of cancer. To date, the best clinical approach for treatment is based on administration of temozolomide (TMZ) in combination with radiotherapy. Much evidence suggests that the intracellular level of the alkylating enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) impacts response to TMZ in GBM patients. MGMT expression is regulated by the methylation of its promoter. However, evidence indicates that this is not the only regulatory mechanism present. Here, we describe a hitherto unknown microRNA-mediated mechanism of MGMT expression regulation. We show that miR-221 and miR-222 are upregulated in GMB patients and that these paralogues target MGMT mRNA, inducing greater TMZ-mediated cell death. However, miR-221/miR-222 also increase DNA damage and, thus, chromosomal rearrangements. Indeed, miR-221 overexpression in glioma cells led to an increase in markers of DNA damage, an effect rescued by re-expression of MGMT. Thus, chronic miR-221/222-mediated MGMT downregulation may render cells unable to repair genetic damage. This, associated also to miR-221/222 oncogenic potential, may poor GBM prognosis.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University ofNaples, Naples, Italy ; IEOS, CNR, Naples, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Quintavalle
authors.forename: Davide
authors.initials: D
authors.lastname: Mangani
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Roscigno
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.forename: Angel
authors.initials: A
authors.lastname: Diaz-Lagares
authors.forename: Margherita
authors.initials: M
authors.lastname: Iaboni
authors.forename: Elvira
authors.initials: E
authors.lastname: Donnarumma
authors.forename: Danilo
authors.initials: D
authors.lastname: Fiore
authors.forename: Pasqualino
authors.initials: P
authors.lastname: De Marinis
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D035683:MicroRNAs; D012333:RNA, Messenger; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins; C525709:MIR221, human; C525710:MIR222, human; C515491:MGMT protein, human