A tRNA-derived fragment from Chinese yew suppresses ovarian cancer growth via targeting TRPA1

Abstract

Drug discovery from plants usually focuses on small molecules rather than such biological macromolecules as RNAs. Although plant transfer RNA (tRNA)-derived fragment (tRF) has been associated with the developmental and defense mechanisms in plants, its regulatory role in mammals remains unclear. By employing a novel reverse small interfering RNA (siRNA) screening strategy, we show that a tRF mimic (antisense derived from the 5 0 end of tRNA His(GUG) of Chinese yew) exhibits comparable anti-cancer activity with that of taxol on ovarian cancer A2780 cells, with a 16-fold lower dosage than that of taxol. A dual-luciferase reporter assay revealed that tRF-T11 directly targets the 3 0 UTR of oncogene TRPA1 mRNA. Furthermore, an Argonaute-RNA immunoprecipitation (AGO-RIP) assay demonstrated that tRF-T11 can interact with AGO2 to suppress TRPA1 via an RNAi pathway. This study uncovers a new role of plant-derived tRFs in regulating endogenous genes. This holds great promise for exploiting novel RNA drugs derived from nature and sheds light on the discovery of unknown molecular targets of therapeutics.

Antitumor Activities of tRNA-Derived Fragments and tRNA Halves from Non-pathogenic Escherichia coli Strains on Colorectal Cancer and Their Structure-Activity Relationship

“…It has been revealed that endogenous tRFs derived from human breast cancer cells could suppress breast cancer in vitro and in vivo by targeting YBX1 mRNA, suggesting that tRFs could target signaling pathways related to cell proliferation, thus enabling an effective intervention with the treatment of cancers ( 28 ). This, together with our previous study on a tRF derived from Chinese yew, which suppresses ovarian cancer by targeting the oncogene TRPA1 ( 31 ), raises the hypothesis that tRFs derived from non-pathogenic E. coli might also function via an RNA interference (RNAi) pathway. Further investigations on the molecular target of EC83 mimics should be performed via mRNA sequencing and experimental validations.…”

“…Double-stranded RNA has been widely employed in investigations on the molecular functions of miRNA or tRF since the double-stranded format is more stable than the single-stranded one ( 30 , 31 ). A total of 82 tRFs, including 5′-tRFs and 3′-tRFs 22 nt in length derived from 41 tRNAs of NPECSs reported in the MODOMICS database and tRNA db ( 25 ) ( Table S1 ), were selected as the antisense strands of tRF mimics in the small interfering RNA (siRNA) form ( Table S2 ) since they are the most abundant types of tRFs ( 32 ).…”

Transfer RNA-derived small RNA: an emerging small non-coding RNA with key roles in cancer

“…In addition, tRF-T11 derived from Chinese redbud can target the 3′-UTR of oncogene TRPA1 mRNA by interacting with AGO2 to suppress TRPA1. This research holds great promise for the development of novel RNA drugs derived from nature [ 31 ].

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Recent advances of non-coding RNAs in ovarian cancer prognosis and therapeutics

“…Plant-derived tRFs-T11 was found to interact with AGO2 to suppress TRPA1 via a RNAi pathway in the A2780 cell, which, in turn, suppresses OC proliferation. 199 Silico analyses and expression profiling were performed using the TCGA-OC database, the GEO dataset, and two institutionally independent cohorts. This analysis highlighted a tRNA GlyGCC-derived internal fragment as a novel molecular predictor of EOC prognosis and supported tRNA may have bright future in the precision medicine decisions in EOC treatment.…”