The Clinical Significance of Transfer RNAs Present in Extracellular Vesicles

Abstract

Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organisms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs present within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1 January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging between 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.

Keywords: cancer; exosome; extracellular vesicle; tRNA fragment; tRNA half; transfer RNA.

Figure 1

Fragmentation of tRNAs into tRFs, tRNA-halves, and internal tRFs. tRNAs are cleaved at the anti-codon loop by enzymes such as angiogenin, Dicer, or RNase Z into either 5′ or 3′-tRNA-halves. tRFs can arise from mature tRNA, pre-tRNA as well as tRNA-halves, and are formed when cleavage occurs at either the D-loop or T-loop. However, the enzymes responsible for tRF production are less well understood.

Figure 2

Types of diseases included in the review and the EV methodologies used. (A) Pie chart showing the primary disease focus of the studies (n = 44) included in the review. Studies which investigated EVs in healthy biofluids or methodology optimisation were not included in the pie chart; (B) Pie chart showing the different EV isolation methodologies used in the protocols investigated (n = 71); (C) Pie chart showing the different types of biofluids used for EV isolation in the protocols investigated (n = 71).

Figure 3

PRISMA flowchart showing the screening process of included articles.