tRNA-derived RNA fragments in cancer: current status and future perspectives

Abstract

Non-coding RNAs (ncRNAs) have been the focus of many studies over the last few decades, and their fundamental roles in human diseases have been well established. Transfer RNAs (tRNAs) are housekeeping ncRNAs that deliver amino acids to ribosomes during protein biosynthesis. tRNA fragments (tRFs) are a novel class of small ncRNAs produced through enzymatic cleavage of tRNAs and have been shown to play key regulatory roles similar to microRNAs. Development and application of high-throughput sequencing technologies has provided accumulating evidence of dysregulated tRFs in cancer. Aberrant expression of tRFs has been found to participate in cell proliferation, invasive metastasis, and progression in several human malignancies. These newly identified functional tRFs also have great potential as new biomarkers and therapeutic targets for cancer treatment. In this review, we focus on the major biological functions of tRFs including RNA silencing, translation regulation, and epigenetic regulation; summarize recent research on the roles of tRFs in different types of cancer; and discuss the potential of using tRFs as clinical biomarkers for cancer diagnosis and prognosis and as therapeutic targets for cancer treatment.

Keywords: Biomarkers; Cancer; Epigenetic regulation; RNA silencing; Translation regulation; tRNA-derived fragments.

Fig. 1

Different types of tRNA-derived RNA fragments produced from either pre-tRNAs or mature tRNAs. The 1-tRF series is produced by RNase Z (or ELAC2) cleavage of the pre-tRNA during the tRNA processing. Mature tRNA can be cleaved in the anticodon loop by ANG to produce 5′-tiRNA and 3′-tiRNA series under stress conditions. The 5′-tRF series is derived from the 5′-end of mature tRNAs by endonucleolytic cleavage and exonuclease digestion in the D-loop. The cleavage in the T-loop results in the production of the 3′-tRF series

Fig. 2

Biological functions of tRFs. (A) RNA splicing. tRFs can affect RNA splicing by targeting the 3′-UTR regions of mRNAs or competitive binding of target mRNAs. (B) Translation regulation. YB-1 binding tRFs repress global translation by displacing translation eukaryotic initiation factor and induce assembly of SGs. tRFs can also regulate translation by interacting with ribosomes. (C) Epigenetic regulation. tRFs can inhibit LTR-retrotransposons or participate in non-coding RNA regulation

Fig. 3

Roles of tRFs in different types of cancer. tRFs are associated with many types of cancer including breast cancer, prostate cancer, leukemia, lung cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, urinary bladder carcinoma, cervical carcinoma, uveal melanoma, and pancreatic cancer. These tRFs can play differing biological functions in different types of cancer

Fig. 4

Mechanisms of action of tRFs in breast cancer. Hypoxia-induced tRNA^Glu, tRNA^Asp, tRNA^Gly, and tRNA^Tyr can interact with YBX1 and suppress breast cancer metastasis. Hypoxia-induced tDR-0009 and tDR-7336 can facilitate the doxorubicin resistance in triple-negative breast cancer cells. tRF3E can inhibit cell proliferation by binding with NCL. 5′-tiRNA^Val inhibits breast cancer progression by directly targeting FZD3 3′-UTR sequence. RUNX1-regulated tRFs and sex hormone-dependent tiRNA (SHOT-RNAs) are associated with cell proliferation