miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS
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Danilo Fiore1, Elvira Donnarumma2, Giuseppina Roscigno1,3, Margherita Iaboni1, Valentina Russo1, Alessandra Affinito1, Assunta Adamo1, Fabio De Martino1, Cristina Quintavalle4, Giulia Romano5, Adelaide Greco6,7, Ylermi Soini8, Arturo Brunetti6,7, Carlo M. Croce5, Gerolama Condorelli1,3
1Department of Molecular Medicine and Medical Biotechnology, “Federico II” University of Naples, Naples, Italy
2IRCCS-SDN, Naples, Italy
3IEOS, CNR, Naples, Italy
4Institute of Pathology, Molecular Pathology Division, University of Basel, Basel, Switzerland
5Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
6Department of Advanced Biomedical Science, University of Naples Federico II, Naples, Italy
7Ceinge, Biotecnologie Avanzate, Scarl, Naples, Italy
8Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
Gerolama Condorelli, e-mail: [email protected]
Keywords: microRNAs, glioblastoma, survival, NRAS, signal-transduction
Received: August 10, 2015 Accepted: January 01, 2016 Published: January 21, 2016
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.
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