Comprehensive analysis of microRNA expression profile in malignant glioma tissues

Abstract

Malignant gliomas represent the most devastating group of brain tumors in adults, among which glioblastoma multiforme (GBM) exhibits the highest malignancy rate. Despite combined modality treatment, GBM recurs and is invariably fatal. A further insight into the molecular background of gliomagenesis is required to improve patient outcomes. The primary aim of this study was to gain broad information on the miRNA expression pattern in malignant gliomas, mainly GBM. We investigated the global miRNA profile of malignant glioma tissues with miRNA microarrays, deep sequencing and meta-analysis. We selected miRNAs that were most frequently deregulated in glioblastoma tissues, as well as in peritumoral areas, in comparison with normal human brain. We identified candidate miRNAs associated with the progression from glioma grade III to glioma grade IV. The meta-analysis of miRNA profiling studies in GBM tissues summarizes the past and recent advances in the investigation of the miRNA signature in GBM versus noncancerous human brain and provides a comprehensive overview. We propose a list of 35 miRNAs whose expression is most frequently deregulated in GBM patients and of 30 miRNA candidates recognized as novel GBM biomarkers.

Keywords: Brain tumors; Glioblastoma; Gliomas; Meta-Analysis; miRNA profiling; microRNA.

Figure 1

Microarray analysis of miRNA expression in GBM tissues and normal human brain. (A) Heat map of the clustered miRNAs that showed significantly different expression in GBM tissues when compared to normal human brain. miRNAs in orange showed strong signal intensity (increased expression), while those in navy blue showed low signal (decreased expression). White – lack of signal (no expression). (B) Heat map displaying the expression of miRNAs that showed distinct profile in the border of glioma in comparison to normal human brain. (C) Venn diagram illustrating the relationships between sets of differentially expressed miRNAs in GBM tissues and borders of tumor in comparison with normal brain. Circles include the total number of differentially expressed miRNAs in the direct pairwise comparison indicated. Intersection area corresponds to the number of differentially expressed miRNAs shared between each comparison. For each group, miRNAs up‐regulated (indicated in red) and down‐regulated (indicated in green) are listed in tables below the diagram. T – glioma tumor tissue; B – border of glioma tissue; N – normal human brain tissue.

Figure 1

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Figure 2

Putative novel miRNA biomarkers of glioblastoma. (A) Venn diagram showing the number of deregulated miRNAs in glioblastoma identified in the current study and in previous GBM profiling studies. The overlapping miRNAs and exclusively identified in our research are indicated below the diagram and colored (red: up‐regulated, green: down‐regulated). Functional relationships of the candidate miRNA biomarkers of glioblastoma and their targets were identified by Ingenuity Pathway Analysis and are presented in (B) the network of ‘Inflammatory Disease, Inflammatory Response, Organismal Injury and Abnormalities’ with IPA score of 31, and (C) ‘Cell Death and Survival, Cellular Development, Cellular Growth and Proliferation’ with IPA score of 7.

Figure 2

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