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Survival in glioblastoma patients is predicted by miR-340, that regulates key cancer hallmarks by inhibiting NRAS

Danilo Fiore, University of Naples, Naples, Italy; Cristina Quintavalle, University Hospital Basel, Basel, Switzerland; Elvira Donnarumma, IRCCS-SDN foundation, Naples, Italy; Giuseppina Roscigno, IEOS, CNR, Naples, Italy; Margherita Iaboni, University of Naples, Naples, Italy; Valentina Russo, University of Naples, Naples, Italy; Assunta Adamo, University of Naples, Naples, Italy; Fabio De Martino, University of Naples, Naples, Italy; Adelaide Greco, University of Naples, Naples, Italy; Giulia Romano, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Soini Ylermi, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Arturo Brunetti, University of Naples, Naples, Italy; Carlo Maria Croce, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Gerolama Condorelli, University of Naples, Naples, Italy

Glioblastoma is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, patients survival remains poor. Nevertheless, a subset of patients survives longer than 3 years and they are classified as long-term survivors (LTS). The molecular and cellular mechanisms underlying the rare phenomenon of LTS are not well known. MicroRNAs (miRNAs or miRs) are a class of endogenous non-coding RNA of 19-24 nucleotides in length that have an important role in the negative regulation of gene expression. Deregulation of miRNAs is linked to the pathogenesis of many types of cancer. We performed a nanostring miRNA analysis on long and short glioblastoma survivors patients to individuate miRs potentially involved in LTS phenotype. Using this approach, we identified miR-340 as a novel tumor-suppressor-miR in glioblastoma. miR-340 expression was increased in LTS compared to short term survivors. Moreover, a log-rank test analysis on both the data collected from TCGA database and from a cohort of glioblastoma patients present in our lab revealed that low levels of miR-340 were a risk indicator for glioblastoma patients survival. miR-340 overexpression decreased cell proliferation, anchorage independent cell growth, cell cycle and response to temozolomide in different glioblastoma cell lines. We identified NRAS as a direct target of miR-340. Rescue experiments showed its essential role in mediating the onco-suppressive activity of miR-340. The overexpression of miR-340 decreased the activation of ERKs and AKT, the main pathways downstream NRAS. Furthermore, glioblastoma cells stably infected with a lentivirus encoding miR-340 exhibited a drastic reduction of tumor growth in nude mice. In conclusion, our findings reveal miR-340 as a new tumor-suppressor miRNA up-regulated in LTS in glioblastoma. Its expression inversely correlates with survival of glioblastoma patients. miR-340 is able to regulate multiple tumorigenic features of glioblastoma cells, offering a novel potential prognostic and therapeutical target for glioblastoma.

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