Do small RNAs have potential in disease diagnosis and treatment?

Ribonucleic acids (RNAs) are very complex and their complete functions are yet to be fully elucidated. Noncoding RNAs having no protein-coding capacity are represented by housekeeping noncoding RNAs: transfer (t)RNA, ribosomal (r)RNA, small nuclear (sn)RNA, and small nucleolar (sno)RNA that are engaged in basic cellular and molecular processes and by regulatory noncoding RNA: short noncoding RNA (<200 nt, sncRNA) and long noncoding RNA (>200 nt, lncRNA) that are important for gene expression/transcript stability. snoRNAs are extensively studied ncRNAs, which are mostly responsible for the post-transcriptional modification and maturation of rRNAs, snRNAs, and other cellular RNAs. Several classes of small RNAs have emerged recently. Numerous aspects of their origins, structures, related effector proteins, and biological roles have led to the identification of three main categories: short interfering (si)RNAs, micro (mi) RNAs, and piwi-interacting (pi)RNAs. These small RNAs are regulated by two recently discovered miRNA-regulatory RNAs, namely competing endogenous (ce)RNA and circular (circ)RNA. Recently, another class of small RNAs (17–18 nt in length) was discovered in animals using deep sequencing approaches and these are found to be associated with transcription initiation (‘tiRNAs’) and splice sites (‘spliRNAs’). Initial studies suggest that they may play a role in nucleosome positioning and/or be involved in chromatin organization. There are also other reports of less distinct classes of promoter-associated RNAs called PASRs, TSSa-RNAs, and PROMPTS, some of which may play a role in RNA-directed transcriptional gene silencing. Discoveries of these sncRNAs have induced a paradigm shift in our overall understanding of gene expression regulation and different signaling pathways. We now understand that coding and noncoding RNA machinery work in concert to maintain overall homeostasis. These RNAs perform diverse functions such as regulating gene expression, splicing, translation, and post-transcriptional modifications. Alterations and personal variations of RNA interactions have been automatically coupled with disease etiology and phenotypical variations. They have also demonstrated clinical significance as potential RNA biomarkers, RNA mimics, and RNA antagonists for early diagnosis, prognosis, and therapeutic targets for several diseases, including cancer [1,2]. Small RNAs are also involved in specifying and stabilizing distinct chromatin states. But lately, it has become obvious that small RNAs can trigger epigenetic gene silencing. Once initiated by primary small RNAs, the repressed states can be propagated across multiple generations. Hence, there is an assumption that small RNAs might be involved in sensing environmental conditions and triggering epigenetic gene expression changes, which is responsible for increased population fitness of an organism. In this situation, epigenetic changes induced by environmental stressors, including reprotoxicants, can explain some trans-generationally transmitted phenotypes in non-Mendelian ways [3]. A little over two decades ago, two main classes of doublestranded (ds)RNA in gene regulation, short-interfering (si)RNA and micro (mi)RNA, differing in biogenesis and modes of target regulation were discovered. siRNAs and miRNAs share many similarities and both are short duplex RNA molecules that exert gene silencing effects at the post-transcriptional level by targeting messenger (m)RNA, yet their mechanisms of action and clinical applications are distinct. They have recently been investigated as novel classes of therapeutic agents for the treatment of a wide range of disorders, including cancers and infections. The major difference between siRNAs and miRNAs is that the former is highly specific with only one mRNA target whereas the latter have multiple targets. The therapeutic approaches of siRNAs and miRNAs are therefore very different. dsRNA triggers RNA interference (RNAi), which is an efficient mechanism for the sequence-specific inhibition of posttranscriptional gene expression. Hence, this homologydependent gene silencing has a great latent role in transcriptional regulation and medicine, as a potential diagnostic and therapeutic agent for a wide range of conditions, including cancer, infectious diseases, and metabolic disorders. Moreover, the siRNAs can be used for therapy as a ‘switch off’ for many causing genes. The role of siRNA in the diagnosis of cancerous cells is still not revealed due to the immediate degradation of siRNAs before they can exert their function. Although the utilization of miRNA and siRNA as biomarkers for diagnosing early stages of diseases is still in the pipeline, it is a fast growing field in the area of diagnostics. Furthermore, some snoRNAs have been used as biomarkers for studying the mechanisms of cell transformation and tumorigenesis. They have been found to be highly expressed in blood, plasma, and serum of cancer patients. The expression profile of snoRNA has been used in classification of B-cell chronic lymphocytic leukemia [4]. On the other hand,