Current Progress on Understanding MicroRNAs in Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is an aggressive grade IV astrocytoma with a 1-year median survival rate despite current treatment modalities. A thorough understanding of the vast genetic aberrations and signaling pathways involved in gliomagenesis as well as heterogeneous clinicopathological presentation remains elusive. The recent discovery of microRNAs (miRs) and their capability of simultaneously regulating multiple downstream genes may play a key role in explaining the complex mechanisms underlying GBM formation. miRs are 19 to 25 nucleotide non-protein-coding small RNA molecules involved in the suppression of mRNA translation. This review will summarize and discuss the most recent findings regarding miRs in GBM including downstream targets, functional effects, and therapeutic potentials. Specifically discussed miRs include miR-7, miR-9/miR-9*, miR-10a/miR-10a*/miR-10b, miR-15b, miR-17-92, miR-21, miR-26a, miR-34a, miR-93, miR-101, miR-124, miR-125a, miR-125b, miR-128, miR-137, miR-146b-5p, miR-153, miR-181a/miR-181b, miR-196a/miR-196b, miR-218, miR-221/miR-222, miR-296, miR-302-367, miR-326, miR-381, miR-451, and let-7a. In addition to gene regulatory roles, miRs have demonstrated significant diagnostic, prognostic, and therapeutic potential. These small molecules may both help in the understanding of GBM and in developing new therapeutic options.

Keywords: GBM; glioma; miR; microarray; review.

Figure 1.

MicroRNA (miR) processing. A multistep process is involved in miR generation. Primary miRs (pri-miRs) are transcribed in the nucleus by RNA polymerase II and form hairpin stem-loop structures. Further processing in the nucleus by the endonuclease Drosha forms preliminary miR (pre-miR). Pre-miR is exported from the nucleus by Exportin-5, where cytosolic processing by Dicer generates mature 21- to 23-nucleotide miR duplexes. Duplexed miR is unwound with the guide or passenger strand loaded into RISC composed of Dicer, TRBP, and Ago2. Full complementarity of the miR to mRNA results in mRNA degradation, while partial complementarity results in transcriptional repression by mRNA sequestration in the cytoplasm. DGCR8/Pasha = double-stranded RNA binding domain protein; RISC = RNA-induced silencing complex; TRBP = HIV-1 TAR RNA binding protein.