Fiore, Danilo (2015) Survival in glioblastoma patients is predicted by miR-340, that regulates key cancer hallmarks by inhibiting NRAS. [Tesi di dottorato]

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Abstract

Glioblastoma (GBM) is the most common primary brain tumor in adults, with a poor prognosis and a survival rate of only 12 months after diagnosis. Long-term survivors (LTS) are a small subgroup of glioblastoma patients characterized by a survival rate longer then 12-14 months. There is an increasing interest in the identification of molecular signatures to predict patient prognosis in GBM and delineate the best therapeutic approach. In this work, we reported miR-340 as a novel prognostic tumor-suppressor miRNA in glioblastoma. We analyzed miRNAs expression in two different cohorts of glioblastoma patients accounting for >500 patients, demonstrating that miR-340 is strongly down-regulated in glioblastoma, while is over-expressed in LTS patients compared to short term survivors (STS). Further, we demonstrated that miR-340 expression predicts a better prognosis of GBM patients. miR-340 overexpression in glioblastoma cells had a strong tumor-suppressive activity in vitro and in vivo in nude mice. Finally, we identified N-RAS as a direct critical target of miR-340, and demonstrated that, through N-RAS, miR-340 negatively influence multiple aspects of glioblastoma tumorigenesis, regulating AKT and ERKs pathways. Taken together, our data suggest that miR-340 is down-regulated in glioblastoma, where it exerts a strong tumor-suppressive effect by regulating N-RAS. Thus, miR-340 may represents a novel potential marker for the diagnosis, prognosis and treatment of GBM.

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