Abstract
MicroRNAs (miRNAs) are short noncoding RNAs that play critical roles in human malignancies and can be used as biomarkers for cancer. Until now, a number of biomarkers for prognosis of glioblastoma (GBM) have been reported in tumor tissues but only a few biomarkers in circulating fluid. Using a custom microarray, we previously identified 19 differentially expressed miRNAs in serum of patients with GBM. In this study, we investigated whether 3 of the 19 miRNAs in serum could be used as prognostic biomarkers for patients with GBM. We first validated the serum levels of 3 candidate miRNAs in an independent cohort of 24 GBM patients and 12 healthy volunteers by real-time quantitative reverse transcription PCR (qRT-PCR), and then evaluated the prognostic value of these miRNAs in a total of 36 GBM patients. The results show that the serum levels of the 3 miRNAs (miR-451a, miR-485-3p and miR-4298) determined by qRT-PCR are significantly different between 24 GBM patients and 12 healthy volunteers (all P <0.05) and are in concordance with the results of microarray analysis. High serum level of miR-451a is correlated with positive tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression (P = 0.040). Survival analysis showed that low serum miR-485-3p level is associated with poor progression-free survival (PFS) (P < 0.004) and overall survival (OS) (P < 0.023). Furthermore, univariate and multivariate Cox analyses demonstrated that that serum miR-485-3p expression is a significant independent prognostic factor for PFS and OS in GBM patients. In conclusion, serum miR-485-3p level is reduced and might be a potential prognostic biomarker in GBM patients.
Highlights
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults
We previously used a microarray-based technique to genome-widely analyze serum miRNA profile and identified 19 miRNAs that have significantly differential expression levels between 22 GBM patients and 8 normal volunteers [19], and the microarray data had been deposited into the GEO database in NCBI website with accession number GSE93850
Of the 3 detected miRNAs, miR-451a level was the highest and miR-4298 level was the lowest among the 19 differentially expressed miRNAs in our previous study. Another miRNA, miR-485-3p, was decreased in serum of GBM patients and selected for validation based on the published data that showed its aberrant expression in human cancer cell lines [24,25,26,27]
Summary
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite advances in treatment, patients with GBM have a very poor outcome with a 5-year overall survival rate of less than 10% [1, 2]. To improve the survival of GBM patients, it is critical to understand the molecular mechanism of GBM development and progression and identify the molecular biomarkers for prognosis and targeted therapy. Many molecular biomarkers for prognosis have been identified from GBM tissues, such as O-6-methylgua-nine-. DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 and 2 (IDH1/2), p53, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and 1p/19q [3]. These biomarkers might be used as targets of gene therapy. Accessible and non-invasive biomarkers, which can be detected in GBM patients with or without surgery, is critical to more effective management of GBM
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