title: miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS.
abstract: Glioblastoma is the most common primary brain tumor in adults; with a survival rate of 12 months from diagnosis. However, a small subgroup of patients, termed long-term survivors (LTS), has a survival rate longer then 12-14 months. There is thus increasing interest in the identification of molecular signatures predicting glioblastoma prognosis and in how to improve the therapeutic approach. Here, we report miR-340 as prognostic tumor-suppressor microRNA for glioblastoma. We analyzed microRNA expression in > 500 glioblastoma patients and found that although miR-340 is strongly down-regulated in glioblastoma overall, it is up-regulated in LTS patients compared to short-term survivors (STS). Indeed, miR-340 expression predicted better prognosis in glioblastoma patients. Coherently, overexpression of miR-340 in glioblastoma cells was found to produce a tumor-suppressive activity. We identified NRAS mRNA as a critical, direct target of miR-340: in fact, miR-340 negatively influenced multiple aspects of glioblastoma tumorigenesis by down-regulating NRAS and downstream AKT and ERK pathways. Thus, we demonstrate that expression of miR-340 in glioblastoma is responsible for a strong tumor-suppressive effect in LTS patients by down-regulating NRAS. miR-340 may thus represent a novel marker for glioblastoma diagnosis and prognosis, and may be developed into a tool to improve treatment of glioblastoma.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fiore
authors.affiliation: IRCCS-SDN, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Donnarumma
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Roscigno
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Iaboni
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Russo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Affinito
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Adamo
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: De Martino
authors.affiliation: Institute of Pathology, Molecular Pathology Division, University of Basel, Basel, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Quintavalle
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Advanced Biomedical Science, University of Naples Federico II, Naples, Italy.|Ceinge, Biotecnologie Avanzate, Scarl, Naples, Italy.
authors.forename: Adelaide
authors.initials: A
authors.lastname: Greco
authors.affiliation: Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.affiliation: Department of Advanced Biomedical Science, University of Naples Federico II, Naples, Italy.|Ceinge, Biotecnologie Avanzate, Scarl, Naples, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.|IEOS, CNR, Naples, Italy.
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000072283:A549 Cells; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D017741:Survivors; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; C570046:MIRN340 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: NRAS; glioblastoma; microRNAs; signal-transduction; survival