MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment.

Keywords: cancer therapy; glioblastoma multiforme; microRNA.

Figure 1

Biogenesis of miRNAs. miRNAs are encoded by nuclear DNA and are transcribed by RNA polymerase II to generate pri‐miRNAs. Pri‐miRNAs then fold into stem‐loop structures via intramolecular base pairing and are cleaved by the microprocessor complex. The resulting long hairpin miRNA precursors, called pre‐miRNAs, are then transported from the nucleus by Exportin‐5. In the cytoplasm, pre‐miRNAs are cleaved by the RNase III enzyme Dicer, to produce miRNA duplexes. The duplexes are then unwound and the guide strands are selected by Argonaute for integration into the RNA‐induced silencing complex (RISC). Within RISC, miRNAs serve as templates for recognizing complementary mRNA molecules, resulting in degradation and/or translational repression of target genes.

Figure 2

miRNA modulation strategies for therapeutic intervention. (A). miRNA inhibition. (1) Antagomirs are synthetic, single‐stranded RNA‐based oligonucleotides that are complementary to mature endogenous miRNAs, allowing for binding and silencing of their targets. (2) miRNA sponges contain multiple binding sites to an miRNA of interest, competitively inhibiting it from binding to its target mRNA. As the binding sites are specific to an miRNA's seed region, sponges can inhibit an entire family of related miRNAs. (B) miRNA mimics are synthetic, double‐stranded RNA molecules that have identical sequences to their naturally occurring equivalents, allowing for restoration or amplification of the activity of a target miRNA.