A functional polymorphism in the pre-miR-146a gene influences the prognosis of glioblastoma multiforme by interfering with the balance between Notch1 and Notch2

The aim of the present study was to evaluate the association between a polymorphism (rs2910164) in the microRNA (miR)-146a precursor and the prognosis of glioblastoma multiforme (GBM), as well as to examine the possible underlying mechanism in a Chinese population. A total-of 380 patients with histologically confirmed GBM were recruited between 2008 and 2012, and were genotyped for the rs2910164 polymorphism using Sanger sequencing. The Kaplan-Meier method was used to estimate overall survival (OS), and univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the effect of miR-146a polymorphisms on OS. It was identified that the rs2910164 CC genotype was significantly associated with a decreased OS among the patients with GBM (P=0.002). It was confirmed that Notch1 and Notch2 were targets of miR-146a and it was demonstrated that the introduction of miR-146a mimic suppressed the levels of Notchl and Notch2 to different extents, resulting in a reduced Notch1/Notch2 ratio with an increase in miR-146a mimic concentration in U251 cells. Additionally, resected tumor specimens were collected from 138 GBM patients and the expression levels of miR-146a, Notchl and Notch2 were examined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Consistent with the in vitro study, lower levels of miR-146a, higher levels of Notch1 and Notch2, and a higher Notch1/Notch2 ratio were identified in the CC genotype group compared with those of the GG/GC group. In the present study, the rs2910164 C allele was found to be associated with a reduced survival rate in patients with GBM, and the observed association between the CC genotype and poorer prognosis of GBM was at least partially mediated by the decreased expression of miR-146a, which interfered with the balance of Notch1 and Notch2.