The Role of miRNAs in Angiogenesis, Invasion and Metabolism and Their Therapeutic Implications in Gliomas

Abstract

MicroRNAs (miRNAs) are small, non-coding, endogenous RNA molecules that function in gene silencing by post-transcriptional regulation of gene expression. The dysregulation of miRNA plays a pivotal role in cancer tumorigenesis, including the development and progression of gliomas. Their small size, stability and ability to target multiple oncogenes have simultaneously distinguished miRNAs as attractive candidates for biomarkers and novel therapeutic targets for glioma patients. In this review, we summarize the most frequently cited miRNAs known to contribute to gliomagenesis and progression by regulating the defining hallmarks of gliomas, including angiogenesis, invasion, and cell metabolism. We also discuss their promising potential as prognostic and predictive biomarkers and novel therapeutic targets, in addition to the challenges that must be overcome before their translation from bench to bedside.

Keywords: angiogenesis; cell metabolism; glioblastoma; glioma; invasion; miRNA.

Figure 1

Biogenesis and regulation of microRNA (miRNA). The transcription of miRNA is regulated by epigenetic mechanisms in addition to other levels. The interplay between DNA hypermethylation and H3 lysine 9 and 20 trimethylation can form condensed and inactive chromatin structures to suppress the transcription of miRNA genes. On the other hand, DNA hypomethylation and loss of H3 lysine 9 and 20 trimethylation will reverse chromatin condensation, resulting in transcription of miRNA genes. The miRNA genes are transcribed by Polymerase II/III into a structure that folds back to form a hairpin loop. This structure is known as a primary-miRNA (pri-miRNA), which is capped and polyadenylated. The pri-miRNA is then recognized and cleaved by a nuclear protein, in complex with Dgcr8/Drosha, to form precursor miRNA (pre-miRNA) in the nucleus, which is transported into the cytoplasm by Exportin-5. The exported pre-miRNA is cleaved by RNAse III enzyme Dicer, in association with the human immunodeficiency virus transactivating response RNA-binding protein (TRBP). The product is an imperfect miRNA: miRNA duplex about 22 nucleotides in length. The duplex is unwound by helicase, after which the strand corresponding to the mature miRNA is loaded onto the RNA-induced silencing complex (RISC). Based on the target and complementarity, mature miRNAs can bind either the 3′-untranslated region of target mRNAs and subsequently block their translation and/or result in mRNA cleavage/degradation or, alternatively, bind to the 5′-UTR region and lead to translational activation.

Figure 2

Strategies for manipulation of miRNAs for therapeutic application. Endogenous miRNAs bind to specific regions in 3′-UTR of the mRNA, in order to degrade their target. (1) Mimics are synthetic oligonucleotide duplexes that can produce a similar effect, and are used if the expression of miRNA is lost due to the malignant state. (2) Oncogenic miRNAs can be downregulated by the use of complimentary miRNAs, known as antagomirs/AMOs (Anti-miRNA oligonucleotides). AMOs (shown in green) bind to their target miRNAs (shown in red), and prevent them from interacting with their target mRNA, thus allowing normal translation. (3) The miRNA mask is a construct that is complementary to the mRNA sequence, intended for the binding of a particular miRNA (shown in bright green). The competitive inhibition thus prevents the miRNA binding and allows the translation of mRNA. (4) miRNA sponges (shown in blue) are transcripts expressed from strong promoters that display multiple miRNA binding sites. They can be engineered to produce a large quantity of transcripts, in order to target a group/family of miRNAs that share a similar seed sequence.