Abstract
Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Base Pairing
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Base Sequence
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / therapy
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Female
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HCT116 Cells
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HEK293 Cells
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HeLa Cells
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Liver Neoplasms / therapy
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Male
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Mice
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / pharmacology
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Oligonucleotides, Antisense / therapeutic use
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Protein Biosynthesis / drug effects
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Protein Biosynthesis / genetics
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RNA, Messenger / chemistry
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Ribosomal, 18S / genetics
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RNA, Ribosomal, 18S / metabolism
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RNA, Small Untranslated / antagonists & inhibitors
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RNA, Small Untranslated / genetics*
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RNA, Transfer, Leu / antagonists & inhibitors
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RNA, Transfer, Leu / genetics*
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Ribosomal Proteins / biosynthesis*
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Ribosomal Proteins / genetics
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Ribosome Subunits, Small, Eukaryotic / metabolism
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Ribosomes / drug effects
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Ribosomes / genetics*
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Ribosomes / metabolism*
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Substrate Specificity / genetics
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Xenograft Model Antitumor Assays
Substances
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Oligonucleotides, Antisense
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RNA, Messenger
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RNA, Ribosomal, 18S
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RNA, Small Untranslated
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RNA, Transfer, Leu
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Ribosomal Proteins