Abstract
BackgroundCurrently, tRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of non-coding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. However, tsRNAs involvement in colorectal cancer (CRC) progression remains unclear.MethodsSequencing analyses were performed to explore the tsRNAs with differential expression in CRC. Gain- and loss-of functions of 5’tiRNA-His-GTG were performed in CRC cells and xenograft tumor to discover its role in the progression of CRC. Hypoxia culture and hypoxia inducible factor 1 subunit alpha (HIF1α) inhibitors were performed to uncover the biogenesis of 5’tiRNA-His-GTG. The regulation of 5’tiRNA-His-GTG for large tumor suppressor kinase 2 (LATS2) were identified by luciferase reporter assay, western blot, and rescue experiments.ResultsHere, our study uncovered the profile of tsRNAs in human CRC tissues and confirmed a specific tRNA half, 5’tiRNA-His-GTG, is upregulated in CRC tissues. Then, in vitro and in vivo experiments revealed the oncogenic role of 5’tiRNA-His-GTG in CRC and found that targeting 5’tiRNA-His-GTG can induce cell apoptosis. Mechanistically, the generation of 5’tiRNA-His-GTG seems to be a responsive process of tumor hypoxic microenvironment, and it is regulated via the HIF1α/angiogenin (ANG) axis. Remarkably, LATS2 was found to be an important and major target of 5’tiRNA-His-GTG, which renders 5’tiRNA-His-GTG to “turn off” hippo signaling pathway and finally promotes the expression of pro-proliferation and anti-apoptosis related genes.ConclusionsIn summary, the findings revealed a specific 5’tiRNA-His-GTG-engaged pathway in CRC progression and provided clues to design a novel therapeutic target in CRC.
Highlights
TRNA-derived small RNAs are recognized as a novel and potential type of noncoding RNAs, which participate in various cellular processes and play an essential role in cancer progression
We identified that 5’tRNA-derived and stress-induced small RNAs (tiRNAs)-HisGTG plays an oncogenic role in colorectal cancer (CRC) progression
5’tiRNA-His-GTG plays an oncogenic role in CRC The expression levels of 5’tiRNA-His-GTG in different CRC cell lines (RKO, SW1116, LoVo, Caco2, SW480, HCT116, and DLD1) were determined using qRT-PCR, and the results showed that 5’tiRNA-His-GTG is highly expressed in HCT116 and LoVo cells, and weakly in RKO cells (Fig. 3a)
Summary
TRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of noncoding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. The low survival rate of patients with advanced CRC indicates that more effective treatments are required [4, 5]. In this regard, the pathological mechanisms driving CRC should be thoroughly investigated to identify novel biomarkers or therapeutic targets. Non-coding RNAs (ncRNAs) have been shown to play critical roles in both cellular function and human disease. Some ncRNAs are stable and detectable in various human biofluids, which can be regarded as potential non-invasive biomarkers in cancers [6]. Advances in oligonucleotide drug delivery make it more available to target ncRNAs against malignant tumors [7]
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