A 3′-tRNA-derived fragment enhances cell proliferation, migration and invasion in gastric cancer by targeting FBXO47
Introduction
Gastric cancer (GC) is one of the most common human cancer types, with an increasing global burden and comprising the second leading cause of cancer-related deaths worldwide [1,2]. Since GC is often diagnosed at an advanced stage, treatment with current surgical, chemical or radiological therapies often cannot improve patient prognosis, resulting in a poor survival rate [[3], [4], [5]]. More effective diagnostic biomarkers to identify GC at earlier stages would benefit GC patients. However, current biomarkers have limitations in specificity and sensitivity [6,7]. Thus, it is imperative to identify novel biomarkers to better diagnose and screen GC patients at an early stage.
tRNA fragments are abundant, heterogeneous, short non-coding RNAs ubiquitous in all domains of life [[8], [9], [10]]. Some studies demonstrate that tRNA fragments are not products of random tRNA degradation, rather they are generated by multiple pre-tRNAs and mature tRNAs undergoing endonucleolytic cleavage with different ribonucleases [[11], [12], [13], [14]]. They are classified into two main groups: tRNA-derived RNA fragments (tRFs) with lengths of 14–36 nt and tRNA halves (tiRNAs) with lengths of 30–40 nt [[15], [16], [17]]. Recent findings have indicated that tRNA fragments can serve as potential biomarkers in breast [[18], [19], [20], [21]], clear cell renal cell [22,23], colorectal [24,25], and prostate cancers [[26], [27], [28]]. Recent studies have implicated that these tRNA-derived fragments play crucial roles in oncogenesis and cancer progression [[29], [30], [31], [32]]. Goodarzi et al. demonstrated that endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement [33]. Moreover, Honda et al. reported that sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers [34]. Furthermore, Kim et al. showed that inhibition of a tRNA-derived small RNA named LeuCAG3′tsRNA impairs ribosome biogenesis and suppresses tumor growth [35]. Thus, these tRNA derivatives have gained increasing attention for human cancer diagnosis and as targets for therapy [30]. Additionally, Li et al. reported that 3′ tRFs inhibit endogenous retroviral replication though binding to the transcribed viral RNA, enabling the rapid cleavage of the transcribed endogenous viral RNA [36]. Recently, Ruggero et al. [37] reported that tRF-3019 (nomenclature based on Lee et al. [15]) corresponds to the 3′ end of tRNA-Pro, which was confirmed to serve as the primer for human T-cell leukemia virus type 1 (HTLV-1) reverse transcriptase and was enriched in virus particles, suggesting a role for tRF-3019 in the life cycle of HTLV-1 [37]. However, any effects of tRFs in GC remain unknown.
In the present study, we used the tRF&tiRNA array to detect abnormally expressed tRNA-derived fragments in GC. We chose the highest upregulated one, tRF-3019a (nomenclature based on tRFdb [38]), for further study. tRF-3019a is derived from the 3′ end of mature tRNA-Ala-AGC-1-1, consists of 18 nt (5′-TCCCCAGTACCTCCACCA-3′), and is located at chr6: 28763741-3 to 28763755. We demonstrated that tRF-3019a directly regulates a predicted target gene, F-box protein 47 (FBXO47), in GC cell lines. Human FBXO47, a member of the F-box family [[39], [40], [41]], is located on chromosome 17q12 and functions as a tumor-suppressor gene [42]. However, the function and regulatory relationship between tRF-3019a and FBXO47 remain vague. We sought to explore their function and regulatory relationship in GC and demonstrated that tRF-3019a-mediated FBXO47 downregulation promotes GC cell malignant activities, indicating that tRF-3019a plays a crucial role in GC by targeting FBXO47.
Section snippets
tRF&tiRNA microarray analysis
Total RNA from ten GC patients’ tumor tissues and matched-paired non-tumor adjacent tissues (NATs) was quantified via microarray using the nrStarTM Human tRF&tiRNA PCR Array (Arraystar, Lnc. Rockville, MD 20850 USA. Cat#: AS-NR-002). Sample preparation and microarray hybridization followed Arraystar standard protocols.
Tissue specimens and cell lines
GC tissues and matched NATs were collected from GC patients undergoing curative surgery between 2016 and 2017 at the First Affiliated Hospital of China Medical University
tRF-3019a is upregulated in GC tissues and cell lines
To identify tRNA fragments with differential expression (defined as fold change > 2 and P < 0.05) in GC tissues compared with NATs, we used the Human tRF&tiRNA PCR Array and found 7 upregulated and 15 downregulated tRNA fragments in GC (Fig. 1A). We chose the highest upregulated one, tRF-3019a (fold change = 3.59, P < 0.05), for further study. As is shown in Fig. 1B, tRF-3019a is derived from the 3′ end of mature tRNA-Ala-AGC-1-1, with the cleavage site located at the T-loop. The qRT-PCR
Discussion
GC develops following a stepwise accumulation of multiple genetic and epigenetic alterations with complicated regulatory interaction networks during tumor initiation and disease progression [43,44]. In the past, tRNA-derived fragments were considered to be products of tRNA degradation [36,45]. The development of microarrays and RNA sequencing technology allowed us to recognize that tRFs have important functions in various biological processes and that they may be important regulators of
Conclusion
In conclusion, our study shows that tRF-3019a is upregulated in GC tissues and cell lines. We identified tRF-3019a as a potential diagnostic biomarker for GC and further demonstrated that tRF-3019a modulates GC cell proliferation, migration and invasion by targeting FBXO47.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (No. 81872031), the Xingliao Talents Program in Liaoning Province (No. XLYC1807164), the China Postdoctoral Science Foundation (No. 2018M640267, 2019T120223), the Scientific and Technological Innovation Talents Program of Shenyang (No. RC190202) and the Project of Science and Technology of Shenyang (No. 18-014-4-07)
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These authors contributed equally to this work.