The number of studies on non-coding RNAs has increased substantially in recent years owing to their importance in gene regulation. However, the biological functions of small RNAs from abundant species of housekeeping non-coding RNAs (rRNA, tRNA, etc.) remain a highly studied topic. tRNA-derived small RNAs (tsRNAs) refer to the specific cleavage of tRNAs by specific nucleases [e.g., Dicer and angiogenin (ANG)] in particular cells or tissues or under certain conditions such as stress and hypoxia. tsRNAs are a type of non-coding small RNA that are widely found in the prokaryotic and eukaryotic transcriptomes and are generated from mature tRNAs or precursor tRNAs at different sites. There are two main types of tsRNAs, tRNA-derived fragments (tRFs) and tRNA halves. tRFs are 14-30 nucleotides (nt) long and mainly consist of three subclasses: tRF-5, tRF-3, and tRF-1. tRNA halves, which are 31-40 nt long, are generated by specific cleavage in the anticodon loops of mature tRNAs. There are two types of tRNA halves, 5'-tRNA halves and 3'-tRNA halves. tsRNAs have multiple biological functions including acting as signaling molecules in stress responses and as regulators of gene expression. Additionally, they have been considered to be involved in RNA processing, cell proliferation, translation suppression, the modulation of DNA damage response, and neurodegeneration. More importantly, they are closely related to the occurrence of many human diseases such as tumors, infectious diseases, metabolic diseases, and neurological diseases. Moreover, tsRNAs have the potential to become new biomarkers for disease diagnosis. Continuous investigations will help us to understand their generation and regulatory mechanisms as well as the possible roles of tRFs and tRNA halves.

Cancer stem cells (CSCs) are thought to drive uncontrolled tumor growth, and the existence of CSCs has recently been proven by direct experimental evidence, including tracing cell lineages within a growing tumor. However, CSCs must be analyzed in additional cancer types. Cancer stem cell-like cells (CSCLCs) are a good alternative system for the study of CSCs, which hold great promise for clinical applications. OCT4, NANOG, and SOX2 are three basic transcription factors that are expressed in both CSCLCs and embryonic stem cells (ESCs). These transcription factors play critical roles in maintaining the pluripotence and self-renewal characteristics of CSCLCs and ESCs. In this review, we discuss the aberrant expression, isoforms, and pseudogenes of OCT4, NANOG, and SOX2 in the CSCLC niche, which contribute to the major differences between CSCLCs and ESCs. We also highlight an anticancer therapy that involves killing specific cancer cells directly by repressing the expression of OCT4, NANOG, or SOX2. Importantly, OCT4, NANOG, and SOX2 provide great promise for clinical applications because reducing their expression or blocking the pathways in which they function may inhibit tumor growth and turn-off the cancer “switch.” In the future, a clear understanding of transcription factor regulation will be essential for elucidating the roles of OCT4, NANOG, and SOX2 in tumorigenesis, as well as exploring their use for diagnostic and therapeutic purposes.

tRNA-derived small RNAs (tsRNAs), including tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs), are small regulatory RNAs processed from mature tRNAs or precursor tRNAs. tRFs and tiRNAs play biological roles through a variety of mechanisms by interacting with proteins or mRNA, inhibiting translation, and regulating gene expression, the cell cycle, and chromatin and epigenetic modifications. The establishment and application of research technologies are important in understanding the biological roles of tRFs and tiRNAs. To study the molecular mechanisms of tRFs and tiRNAs, researchers have used a variety of bioinformatics and molecular biology methods, such as microarray analysis, real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR); Northern blotting; RNA sequencing (RNA-seq); cross-linking, ligation and sequencing of hybrids (CLASH); and photoactivatable-ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP). This paper summarizes the classification, action mechanisms, and roles of tRFs and tiRNAs in human diseases and the related signal transduction pathways, targeted therapies, databases, and research methods associated with them.

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