RNA-Directed Therapy: The Next Step in the miRNA Revolution

Abstract

RNA, once regarded as merely a messenger molecule in the process of gene expression, has recently emerged as a promising target for cancer therapy (reviewed in [1]). A major role for RNA in eukaryotes is carrying a DNA message from the cell nucleus to the cytoplasm, where it provides a template for protein synthesis. However, the recent discovery of small RNAs or microRNAs (miRNAs) that regulate the function and stability of messenger RNAs (mRNAs) has provided new roles for RNA regulating cell processes. Additionally, small RNAs are being exploited as a tool in systems biology to understand gene regulatory networks. We have just returned from a Forbeck Foundation Forum (http://www.wgfrf.org), held annually in Hilton Head Island, South Carolina, at which 16 leaders in the miRNA field talked about their latest work. Theirs is a message that deserves the widest circulation, for it portends a major change in our concepts of the origins, diagnosis, and treatment of cancer. These small RNAs may prove “imperial” like the diminutive Napoleon Bonaparte who was also short . . . but mighty. Instructions for about 20,000 protein-coding genes are contained in the DNA sequence of the human genome. mRNAs are strands of hundreds to thousands of nucleotides that serve as templates for synthesis of proteins by ribosomes found in the cytoplasm. Translation into proteins may be affected by several factors, including amino acid availability, the levels of specific proteins involved in translation, and feedback effects of the coded proteins. Regulation of translation has mainly been ascribed to interactions between proteins and the noncoding portions of the mRNA itself. It has generally been thought that these proteins were solely responsible for control of translation. Now, evidence is mounting that miRNAs bind to these noncoding regions of mRNA and exert profound effects on protein synthesis and consequently cell functions. The implications for cancer are astonishing. First discovered 14 years ago in Caenorhabditis elegans [2, 3], a primitive worm, miRNAs may target at least one third of all mRNAs. On average, each of the approximately 600 miRNAs found in mammalian cells contains partial sequence homology to 100–200 mRNAs. miRNAs have been implicated in the regulation of a diversity of processes, such as Band T-cell development, antigen response, immune surveillance and tolerance, and other basic functions such as cell proliferation and death. In distinction to artificially synthesized small interfering RNAs, which target a single mRNA and cause its digestion by endonucleases, miRNAs target multiple mRNAs through partial sequence complementarity and function primarily by inhibiting protein translation (Fig. 1). However, new work by a Yale team has added a new dimension, suggesting that, in synchronously replicating cells, miRNAs may reverse course and become stimulatory to RNA translation [4]. Recent work from several laboratories has revealed that, in the development of lymphoid cells from undifferentiated precursors to mature antigen responders, specific miRNAs