The Influence of Distinct Regulatory miRNAs of the p15/p16/RB1/E2F Pathway on the Clinical Progression of Glioblastoma Multiforme

World Neurosurg. 2019 Dec:132:e900-e908. doi: 10.1016/j.wneu.2019.07.134. Epub 2019 Jul 24.

Abstract

Objective: The microRNAs (miRNAs) -26a, -24, and -21 have been reported as regulators of the P15/P16/RB1/E2F pathway, which plays a major role in glioblastoma multiforme (GBM) progression. In the present study, their predictive marker for the progression of GBMs is evaluated and described.

Methods: The expression of miRNA-21, -24, and -26a was analyzed as fold change (FC) in tumor specimens of 104 patients with GBM and 8 specimen of non-neoplastic brain tissue as control group. The results were referred to the individual clinical data sets and evaluated statistically.

Results: The FC of miRNA-21, -24, and -26a was 1.51 ± 1.35, 0.75 ± 0.67, and 0.39 ± 0.24 in the tumor samples. Within the control group, FC of miRNA-21, -24, and -26a was 0.31 ± 0.51, 0.66 ± 0.33, and 0.18 ± 0.11, respectively. MiRNA-26a and -21 were significantly overexpressed in GBM samples compared with healthy brain tissue (miRNA-21: P < 0.001; miRNA-26a: P = 0.011). High expression ofmiRNA-24 trended for a prolonged overall survival (P = 0.07). Patients with high miRNA-26a expression showed a significantly prolonged progression-free survival (hazard ratio 0.21; 95% confidence interval 0.09-0.51], P < 0.001) and overall survival (hazard ratio 0.3; 95% confidence interval 0.136-0.682], P = 0.003). The effect of miRNA-26a was mediated via regulation of mRNA of RB1. There was a significant inverse correlation between mRNA-26a and mRNA expression of RB1.

Conclusions: The expression levels of miRNA-26a and -24 turned out to be promising predictors of further clinical course in patients with GBM multiforme.

Keywords: Clinical; Epigenetic; Glioblastoma multiforme; Prognosis; microRNA.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / genetics*
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Methylation
  • Disease Progression
  • E2F Transcription Factors / genetics
  • Female
  • Gene Regulatory Networks
  • Glioblastoma / genetics*
  • Humans
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Prognosis
  • Progression-Free Survival
  • Proportional Hazards Models
  • Retinoblastoma Binding Proteins / genetics
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • E2F Transcription Factors
  • MIRN21 microRNA, human
  • MIRN24 microRNA, human
  • MIRN26A microRNA, human
  • MicroRNAs
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Ubiquitin-Protein Ligases