MicroRNA and brain tumors: a cause and a cure?

Abstract

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modal treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis remains dismal for patients diagnosed with these tumors. With the discovery of RNA interference (RNAi) for target-specific gene silencing via small interfering RNA (siRNA), a novel method to target malignant gliomas has been exposed, an endeavor that is aggressively being carried out in numerous laboratories. However, practical difficulties in tissue- or organ-specific targeting of therapeutic quantities of siRNA still preclude its applicability in a clinical setting. MicroRNA (miRNA), an endogenously expressed form of siRNA, not only presents an alternate method to induce RNAi in a given diseased tissue or organ, but also exposes a unique set of diagnostic markers that can be used to identify, and then differentiate between tumor grades. Thus, miRNA can be considered the cells' answer to siRNA. Discovered over a decade ago, miRNA is fast becoming recognized as crucial in regulating gene expression in cancers. Therein lies the therapeutic potential of miRNA, as it may now be possible to induce or inhibit RNAi in a given diseased cell population by controlling the cells' miRNA expression profile. This review outlines the potential of miRNA as a therapeutic strategy against high-grade gliomas, and also the technological hurdles that need to be addressed before this promising technique can be administered in a clinical setting.

FIG. 1

Biogenesis of miRNA. Current research indicates two schemes for biosynthesis of miRNA: via nonprotein-coding “transcription units” (termed exonic-miRNA genes), and those encoded within introns of protein-coding genes (termed intronic miRNA). Each exonic miRNA gene, or a given intron spliced from pre-mRNA, can give rise to multiple miRNAs, each targeting a different set of mRNA transcripts.

FIG. 2

Possible pathways for therapeutic targeting of miRNA genes: Three schema can be visualized for therapeutic targeting: (A) Recombinant virions capable of integrating into the genome can be used as a therapeutic vehicle to replace “tumor-suppressor-type” miRNA genes that were lost due to genomic instability, or to introduce miRNA-generating constructs that can target specific genes; (B) Small-molecule drugs or growth factor components can be applied to activate specific miRNA gene promoters to activate or upregulate tumor-suppressor-type genes; (C) Small-molecule drugs can be designed to target “oncogenic-type” miRNA gene promoters to inhibit transcription, or they can be designed to target pre-miRNA themselves via intercalation or cross-linking. However, at present, the paucity of information on cis-elements of miRNA gene promoters, or the solution structure of pri-miRNA or pre-miRNA, remains to be overcome for schemes B and C to be of therapeutic utility.