Abstract
BackgroundtRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive.MethodsPapillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed.ResultsHerein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent.ConclusionsOur study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing.
Highlights
TRNA-derived small noncoding RNAs are mainly categorized into tRNA halves and fragments
Our study firstly illustrates tRNA halves (tiRNA)-Gly can directly bind to RNA binding motif protein 17 (RBM17) and display oncogenic effect via RBM17-mediated alternative splicing
After normalization as previously described [17], 1723 tRNA fragments were identified in three pairs of tumor tissues (T) and their adjacent tissues (AT) (Fig. 1A); among these tRNA fragments, 594 tRNA fragments were detected in only tumor samples while 136 were detected in only ATs (Fig. 1B)
Summary
TRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Honda et al firstly unveiled a new tiRNA, sex hormone-dependent tRNA-derived RNAs (SHOTRNAs), could enhance cell proliferation in breast and prostate cancers, which was hormone and receptordependent [4]. These evidences have showed that tiRNAs may be involved in tumorigenesis in hormonedependent cancers. Several 5′-tiRNAs expression patterns have been identified in clear cell renal cell carcinoma. They were inversely correlated with tumor stage and grade [5, 6]. Whether tiRNAs could directly combine with proteins and further regulate the function of its protein partners in tiRNAs-mediated tumorigenesis are largely unknown
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