Non-coding RNAs: a key to future personalized molecular therapy?

Abstract

Continual discoveries on non-coding RNA (ncRNA) have changed the landscape of human genetics and molecular biology. Over the past ten years it has become clear that ncRNAs are involved in many physiological cellular processes and contribute to molecular alterations in pathological conditions. Several classes of ncRNAs, such as small interfering RNAs, microRNAs, PIWI-associated RNAs, small nucleolar RNAs and transcribed ultra-conserved regions, are implicated in cancer, heart diseases, immune disorders, and neurodegenerative and metabolic diseases. ncRNAs have a fundamental role in gene regulation and, given their molecular nature, they are thus both emerging therapeutic targets and innovative intervention tools. Next-generation sequencing technologies (for example SOLiD or Genome Analyzer) are having a substantial role in the high-throughput detection of ncRNAs. Tools for non-invasive diagnostics now include monitoring body fluid concentrations of ncRNAs, and new clinical opportunities include silencing and inhibition of ncRNAs or their replacement and re-activation. Here we review recent progress on our understanding of the biological functions of human ncRNAs and their clinical potential.

Figure 1

Schematic overview of miRNA processing and functions in cancer. Transcription from miRNA genes is under the regulation of transcription factors (TF) that respond to multiple signals and can also be epigenetically controlled. miRNA genes are transcribed by RNA polymerase II to produce a long nucleotide sequence, the pri-miRNA, which is cleaved by Drosha, a RNAse III endonuclease that recognizes internal hairpin structures. The resulting miRNA precursors (pre-miRNAs) of approximately 70 nucleotides are actively exported by Exportin-5 into the cytoplasm. Once in the cytoplasm, the pre-miRNAs are further digested by Dicer (another RNAse III endonuclease), which yields 21 to 22 nucleotide dsRNAs with two nucleotide overhangs (the miRNA* species is a rare non-miRNA cleavage product). Single strands from these dsRNAs associate with several members of the Argonaute (AGO) protein family to form the RNA induced silencing complex (RISC). The mRNA segments that miRNAs bind seem to be mostly in the 3' UTRs. Overexpression (up arrow) of a miRNA could result in downregulation of a tumor suppressor, or underexpression (down arrow) of a miRNA could lead to upregulation of an oncogene. These events thus promote cell proliferation, decrease apoptosis and stimulate angiogenesis, leading to tumorigenesis.