Molecular pathways: microRNAs as cancer therapeutics

Abstract

MicroRNAs (miRNA) are approximately 18 to 25 nucleotides in length and affect gene expression by silencing the translation of messenger RNAs. Because each miRNA regulates the expression of hundreds of different genes, miRNAs can function as master coordinators, efficiently regulating and coordinating multiple cellular pathways and processes. By coordinating the expression of multiple genes, miRNAs are responsible for fine-tuning the cell's most important processes, like the ones involved in cellular growth and proliferation. Dysregulation of miRNAs appears to play a fundamental role in the onset, progression and dissemination of many cancers, and replacement of downregulated miRNAs in tumor cells results in a positive therapeutic response. Thus, in theory, inhibition of a particular miRNA linked to cancer onset or progression can remove the inhibition of the translation of a therapeutic protein-and conversely, administration of a miRNA mimetic can boost the endogenous miRNA population repressing the translation of an oncogenic protein. Although several basic questions about their biologic principles still remain to be answered, and despite the fact that all data with respect to miRNAs and therapy are still at the preclinical level, many specific characteristics of miRNAs in combination with compelling therapeutic efficacy data have triggered the research community to start exploring the possibilities of using miRNAs as potential therapeutic candidates.

Figure 1

MiRNAs are transcribed mainly by RNA polymerase II into an immature form of about 80 nt in length called primary microRNAs (pri-miRNA; ref. 3). The stem loop structure of the pri-miRNA is recognized in the nucleus by Drosha and its partner DGCR8 and it is further processed to the precursor miRNA (pre-miRNA; ref. 3). The hairpin shaped pre-miRNA is then transported from the nucleus to the cytoplasm by exportin-5 (XPO5) where it is loaded by the Dicer-TRBP complex and cleaved into a double-stranded miRNA in a process known as dicing (3). After strand separation the mature miRNA, in combination with Argonaute proteins, form the RNA-induced silencing complex (RISC; ref. 4). The expression of the target mRNAs is silenced by miRNAs on the RISC complex, either by mRNA cleavage or by translational repression (4).