Abstract LB-390: A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular carcinoma

Abstract

Abstract There are tens of thousands of different transfer RNA-derived small RNAs (tsRNAs) of 18-40 nucleotides in length in mammalian cells. In recent years there is accumulating evidence suggesting that these RNAs can play different yet important roles in gene regulations. Nevertheless, in most cases, the biological roles of these RNAs have yet to be defined. Using a variety of locked nucleic acid/antisense oligonucleotide (LNA/ASO)-mediated strategies, we found that inhibition of one specific 3'tsRNA, induces apoptosis in rapidly dividing cells. Inhibition of the tsRNA but not the mature tRNA reduced the translation of ribosomal protein S28 (RPS28) and S15 (RPS15) mRNAs and led to a block in pre-18S ribosomal RNA processing, and ultimately a decrease in the number of 40S ribosomal subunits. Using a modified ChIRP method, we found that the tsRNA binds to ribosomal protein S28 mRNA and by genetic complementation analyses established the binding sites contained within the mRNAs. Furthermore, we established that tsRNA binds to duplexed target sites in RPS28 and RPS15 mRNAs and enhances their translation by perhaps helping to unfold their secondary structures. The systemic delivery of a specific anti-tsRNA oligonucleotides into mice (the tsRNA sequence is the same in mouse and humans) did not cause liver injury in normal mice but induced apoptosis and a significant growth retardation of patient-derived orthotopic hepatocellular carcinomas surgically implanted into mouse livers. Our result establishes a newly defined post-transcriptional mechanism of gene regulation and provides a novel target for cancer therapeutics. Citation Format: Hak Kyun Kim, Gabriele Fuchs, Shengchun Wang, Wei Wei, Yue Zhang, Hyesuk Park, Biswajoy Roy-Chaudhuri, Pan Li, Jianpeng Xu, Kirk Chu, Feijie Zhang, Mei-sze Chua, Samuel So, Cliff Zhang, Peter Sarnow, Mark A. Kay. A transfer RNA derived small RNA affects translation in rapidly dividing cells and a target for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-390.