The Frontiers for Toxicology Session: Noncoding RNAs in Human Health, Therapeutics, and Environmental Disease, was presented on March 25, 2014 at the Society of Toxicology 53rd Annual Meeting in Phoenix, Arizona. A summary of this session is provided below.
Noncoding RNAs are conceptual newcomers to the world of ribonucleic acids, with long non-coding RNAs (lncRNA) and micro-RNAs (miRNA) joining the realms of the more well-described message, transfer, and ribosomal variants. The term “non-coding” used herein indicates that these forms of RNA are not translated into proteins, i.e., unlike message RNA (mRNA) they do not transmit a genetic “code” from the DNA that is later translated into protein form. However, this should not be interpreted to mean that they are simply “nonsense”, or “junk” sequences (typical terms for regions of DNA that do not “code” for known mRNA or protein sequences), for they appear to elicit a variety of effects.
While miRNA are structurally simple and typically consist of 18–22 nucleotides, the lncRNAs can form complex loop and knot regions, among other structural patterns, and stretch for kilobases in length. For lncRNA, this amazing complexity contributes to the variety of functional interactions being uncovered for this emerging regulator of homeostasis and disease, as the variability in secondary and tertiary structures (i.e., physical conformation beyond the linear sequence of ribonucleotides) permits the association or binding with DNA, other forms of RNA, and proteins. Several lncRNAs are highly conserved among primate species, and many lncRNAs appear to frequently associate with chromatin-modifying complexes. Furthermore, lncRNAs may be one mediator of epigenetic memory, and in this capacity could serve as a logical target for epigenome-environment interactions—an area of ongoing research in this field.
While miRNAs do not have the higher order structural complexity of their larger lncRNA cousins, many sequences are highly conserved across mammals and other species, suggesting that they perform critical functions in a sequence-specific manner. The best known activity of miRNAs revolves around the suppression of specific mRNA sequence translation into protein, by either physically blocking translation machinery or via activation of the RISC/Dicer complex and degradation of the target mRNA. However, and somewhat paradoxically, miRNA also have been shown to increase the translation of some targets by binding to and stabilizing the mRNA, which allows for increased amounts of protein synthesis. In addition to effects internal to the cells in which the miRNAs are transcribed, evidence also is emerging that miRNAs can be selectively loaded into lipid vesicles called “exosomes” and secreted in an endocrine or paracrine manner, to be endocytosed by neighboring cells of similar or different types. For example, exosomes secreted by epithelial cells could be taken up and processed in the endosomes of neighboring macrophages, exerting some type of signaling effect on the nearby leukocytes. Evidence for this type of interaction has been demonstrated in mice, where the presence of several miRNA sequences in exosomes regulated the extent of mouse lung colonization by injected tumor cells.
Emerging research is suggesting that miRNA dysregulation is ubiquitous in human malignancies, including both epithelial and lymphatic cancers. Panels of several miRNA species appearing in human blood appears to be able to distinguish healthy individuals from those with cirrhotic or carcinoma-bearing livers with high sensitivity and specificity. Work in mouse models of hepatocellular carcinoma (HCC) has demonstrated that therapeutic expression of particular miRNA sequences greatly reduces tumor growth and malignancy by selectively inducing apoptosis in the neoplastic cells. Taken with the above, research into non-coding RNA species is unearthing numerous possibilities for interaction in both physiological and pathological process, and holds great therapeutic potential for the detection and possible abrogation of human disease.