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.
Highlights
Malignant glioma is the most common and aggressive primary brain tumor [1, 2]
To identify miRNAs de-regulated in long- vs shortterm GBM survivors, we profiled the miRNA signatures of primary GBM tissue harvested from 3 long-term survivors (LTS) and 3 short-term survivors (STS) patients
Because adjuvant chemotherapy with temozolomide is limited by the action of O-6-methylguanine-DNA methyltransferase (MGMT), a contributing factor for very poor survival in GBM patients [28], we investigated a possible role of miR-340 in TMZ sensitivity
Summary
Malignant glioma (glioblastoma or GBM) is the most common and aggressive primary brain tumor [1, 2]. Despite continuous improvement in treatment approaches, with a combination of surgery, radiotherapy and chemotherapy, average survival of GBM patients has improved only slightly [3]. GBM patients tend to have an extremely poor prognosis, with a median survival rate from diagnosis ranging from 12 to 14 months [4, 5]. Different factors are involved in GBM aggressiveness and poor prognosis, such as rapid cell proliferation, resistance to drug-induced apoptosis and enhanced invasiveness. The www.impactjournals.com/oncotarget molecular events associated with the LTS phenotype are not well elucidated. Better understanding of these events would be critical for the development of early detection methods, identification of new biomarkers, and improved therapeutic approaches
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