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Advances in the study of tsRNA as diagnostic and prognostic biomarkers in cancer

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  • Central Laboratory, Nanjing First Hospital, Nanjing Medical Universtiy, Nanjing 210006, China

Received date: 2023-10-23

  Online published: 2024-03-15

Abstract

Transfer RNA (tRNA) promotes the protein translation process by binding with corresponding amino acids and transporting them to the ribosome, emphasizing the vital role of tRNA in protein translation. Transfer RNA-derived small RNA (tsRNA) are fragments originating from tRNA and are produced when these tRNA are cleaved. As the degradation products of tRNA, tsRNA retain significant biological functions, notably in regulating gene expression and modulating translation. Recent researches have highlighted the dual regulatory role of tsRNA in oncology, especially their pronounced variations in the bodily fluids of cancer patients, accentuating the potential of tsRNA as biomarkers for cancer diagnosis and prognosis. Upregulation of tsRNA and 5'tiRNA His GTG related to colorectal cancer promotes tumor occurrence and development; Upregulation of 5 '-tiRNA Val generated by angiopoietin cleavage promotes tumor metastasis and growth; Upregulation of tRF-20-MEJB5Y13 promotes the migration and invasion of colorectal cancer cells. Upregulation of gastric cancer related tsRNA, tRF-19-3L7L73JD, can promote the progression of malignant tumors, while upregulation of tRF-24-V29K9UV3IU, tRF-5026a, and tRF-Val may inhibit tumor proliferation and progression. In terms of clinical application, the expression of plasma 5-tRF-GlyGCC is increased, and the area under the curve for diagnosing colorectal cancer is 0.882. The plasma tRF-5026a is decreased, and the area under the curve for diagnosing colorectal cancer is 0.883. The expression of tRF-27-FDXXE6XRK45, tRF-29-R9J8909NF5JP, and tRF-23-Q99P9P9NDD in the serum of gastric cancer patients was significantly increased. The area under the diagnostic curve for gastric cancer was 0.805, 0.889, and 0.783, respectively; The serum tDR ‐ 000620 in triple negative breast cancer decreased, which was related to lymph node metastasis and disease recurrence. In the plasma exosomes of gastric cancer patients, the expression of tRF-38, tRF-25, and tRF-18 is elevated, which can be used for diagnosis and may be a postoperative predictive factor. The expression levels of tRNA ValTAC-3, tRNA GlyTCC-5, tRNA ValAAC-5, and tRNA GluCTC-5 in the plasma exosomes of liver cancer patients have significantly increased, which may be emerging biomarkers.This article reviews the biogenesis, classification, and biological functions of tsRNA, emphasizing the advancements in their application as tumor biomarkers and delineating their roles across various cancer types, offering insights into their utility in oncological research and clinical applications.

Cite this article

WANG Shukui, GU Xinliang . Advances in the study of tsRNA as diagnostic and prognostic biomarkers in cancer[J]. Journal of Diagnostics Concepts & Practice, 2023 , 22(05) : 413 -420 . DOI: 10.16150/j.1671-2870.2023.05.001

References

[1] HAYNE C K, SCHMIDT C A, HAQUE M I, et al. Reconstitution of the human tRNA splicing endonuclease complex: insight into the regulation of pre-tRNA cleavage[J]. Nucleic Acids Res, 2020, 48(14):7609-7622.
[2] SCHAFFER A E, PINKARD O, COLLER J M. tRNA Metabolism and Neurodevelopmental Disorders[J]. Annu Rev Genomics Hum Genet, 2019, 20:359-387.
[3] ZHU C, SUN B, NIE A, et al. The tRNA-associated dysregulation in immune responses and immune diseases[J]. Acta Physiol (Oxf), 2020, 228(2):e13391.
[4] SHEN Y, YU X, ZHU L, et al. Transfer RNA-derived fragments and tRNA halves: biogenesis, biological functions and their roles in diseases[J]. J Mol Med (Berl), 2018, 96(11):1167-1176.
[5] GIEGé R. Toward a more complete view of tRNA biology[J]. Nat Struct Mol Biol, 2008, 15(10):1007-1014.
[6] RODNINA M V, WINTERMEYER W. The ribosome as a molecular machine: the mechanism of tRNA-mRNA movement in translocation[J]. Biochem Soc Trans, 2011, 39(2):658-662.
[7] KIM H K, YEOM J H, KAY M A. Transfer RNA-Derived Small RNAs: Another Layer of Gene Regulation and Novel Targets for Disease Therapeutics[J]. Mol Ther, 2020, 28(11):2340-2357.
[8] BOREK E, BALIGA B S, GEHRKE C W, et al. High turnover rate of transfer RNA in tumor tissue[J]. Cancer Res, 1977, 37(9):3362-3366.
[9] SPEER J, GEHRKE C W, KUO K C, et al. tRNA breakdown products as markers for cancer[J]. Cancer, 1979, 44(6):2120-2123.
[10] ZHU L, GE J, LI T, et al. tRNA-derived fragments and tRNA halves: The new players in cancers[J]. Cancer Lett, 2019, 452:31-37.
[11] XIE Y, YAO L, YU X, et al. Action mechanisms and research methods of tRNA-derived small RNAs[J]. Signal Transduct Target Ther, 2020, 5(1):109.
[12] RODNINA M V, WINTERMEYER W. The ribosome as a molecular machine: the mechanism of tRNA-mRNA movement in translocation[J]. Biochem Soc Trans, 2011, 39(2):658-662.
[13] ZHU P, YU J, ZHOU P. Role of tRNA-derived fragments in cancer: novel diagnostic and therapeutic targets tRFs in cancer[J]. Am J Cancer Res, 2020, 10(2):393-402.
[14] KATSARAKI K, ARTEMAKI P I, PAPAGEORGIOU S G, et al. Identification of a novel, internal tRNA-derived RNA fragment as a new prognostic and screening biomarker in chronic lymphocytic leukemia, using an innovative quantitative real-time PCR assay[J]. Leuk Res, 2019, 87:106234.
[15] KUMAR P, ANAYA J, MUDUNURI S B, et al. Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets[J]. BMC Biol, 2014, 12:78.
[16] 朱林文, 谢依, 郭俊明. tRNA衍生片段和tRNA半分子的生物学功能及其在疾病发生中的作用[J]. 生物化学与生物物理进展, 2017, 44(7):565-572.
  ZHU L W, XIE Y, GUO J M. The biological functions of tRNA-derived fragments and trna halves, and their roles in the pathogenesis[J]. Prog Biochem Biophys, 2017, 44(7).
[17] COLE C, SOBALA A, LU C, et al. Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs[J]. RNA, 2009, 15(12):2147-2160.
[18] PARK E J, KIM T H. Fine-tuning of gene expression by tRNA-derived fragments during abiotic stress signal transduction[J]. Int J Mol Sci, 2018, 19(2):518.
[19] LI S, XU Z, SHENG J. tRNA-derived small RNA: a novel regulatory small non-coding RNA[J]. Genes (Basel), 2018, 9(5):246.
[20] LI S, HU G F. Emerging role of angiogenin in stress response and cell survival under adverse conditions[J]. J Cell Physiol, 2012, 227(7):2822-2826.
[21] LI S, SHI X, CHEN M, et al. Angiogenin promotes colorectal cancer metastasis via tiRNA production[J]. Int J Cancer, 2019, 145(5):1395-1407.
[22] ANDERSON P, IVANOV P. tRNA fragments in human health and disease[J]. FEBS Lett, 2014, 588(23):4297-4304.
[23] SAIKIA M, HATZOGLOU M. The many virtues of tRNA-derived stress-induced RNAs (tiRNAs): discovering novel mechanisms of stress response and effect on human health[J]. J Biol Chem, 2015, 290(50):29761-29768.
[24] HE L, HANNON G J. MicroRNAs: small RNAs with a big role in gene regulation[J]. Nat Rev Genet, 2004, 5(8):631].
[25] TONG L, ZHANG W, QU B, et al. The tRNA-derived fragment-3017A promotes metastasis by inhibiting NELL2 in human gastric cancer[J]. Front Oncol, 2021, 10:570916.
[26] CAO K Y, YAN T M, ZHANG J Z, et al. A tRNA-derived fragment from Chinese yew suppresses ovarian cancer growth via targeting TRPA1[J]. Mol Ther Nucleic Acids, 2022, 27:718-732.
[27] LI J, ZHU L, CHENG J, et al. Transfer RNA-derived small RNA: a rising star in oncology[J]. Semin Cancer Biol, 2021, 75:29-37.
[28] GOODARZI H, LIU X, NGUYEN H C, et al. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement[J]. Cell, 2015, 161(4):790-802.
[29] KRISHNA S, YIM D G, LAKSHMANAN V, et al. Dynamic expression of tRNA-derived small RNAs define cellular states[J]. EMBO Rep, 2019, 20(7):e47789.
[30] ZHAO R, YANG Z, ZHAO B, et al. A novel tyrosine tRNA-derived fragment, tRFTyr, induces oncogenesis and lactate accumulation in LSCC by interacting with LDHA[J]. Cell Mol Biol Lett, 2023, 28(1):49.
[31] YANG W, GAO K, QIAN Y, et al. A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes[J]. J Hematol Oncol, 2022, 15(1):53.
[32] SHI J, ZHANG Y, ZHOU T, et al. tsRNAs: The swiss army knife for translational regulation[J]. Trends Biochem Sci, 2019, 44(3):185-189.
[33] GEBETSBERGER J, WYSS L, MLECZKO A M, et al. A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress[J]. RNA Biol, 2017, 14(10):1364-1373.
[34] KUMAR P, ANAYA J, MUDUNURI S B, et al. Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets[J]. BMC Biol, 2014, 12:78.
[35] MAUTE R L, SCHNEIDER C, SUMAZIN P, et al. tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma[J]. Proc Natl Acad Sci U S A, 2013, 110(4):1404-1409.
[36] KIM H K, FUCHS G, WANG S, et al. A transfer-RNA-derived small RNA regulates ribosome biogenesis[J]. Nature, 2017, 552(7683):57-62.
[37] KIM H K, XU J, CHU K, et al. A tRNA-derived small RNA regulates ribosomal protein S28 protein levels after translation initiation in humans and mice[J]. Cell Rep, 2019, 29(12):3816-3824.e4.
[38] LYONS S M, GUDANIS D, COYNE S M, et al. Identification of functional tetramolecular RNA G-quadruplexes derived from transfer RNAs[J]. Nat Commun, 2017, 8(1):1127.
[39] AKIYAMA Y, KHAREL P, ABE T, et al. Isolation and initial structure-functional characterization of endogenous tRNA-derived stress-induced RNAs[J]. RNA Biol, 2020, 17(8):1116-1124.
[40] YAN Q, ZHU C, GUANG S, et al. The functions of non-coding RNAs in rRNA regulation[J]. Front Genet, 2019, 10:290.
[41] 中华人民共和国国家卫生健康委员会. 中国结直肠癌诊疗规范(2023版)[J]. 中华消化外科杂志, 2023, 22(6):667-698.
  National Health Commission of the People′s Republic of China. Chinese protocol of diagnosis and treatment of colorectal cancer (2023 edition)[J]. Chin J Dig Surg, 2023, 22(6):667-698.
[42] 中华人民共和国国家卫生健康委员会医政医管局. 胃癌诊疗指南(2022年版)[J]. 中华消化外科杂志, 2022, 21(9):1137-1164.
  Bureau of Medical Administration, National Health Commission of the People′s Republic of China. Standardization for diagnosis and treatment of gastric cancer (2022 edition)[J]. Chin J Dig Surg, 2022, 21(9):1137-1164.
[43] 赫捷, 陈万青, 李兆申, 等. 中国胃癌筛查与早诊早治指南(2022,北京)[J]. 中华消化外科杂志, 2022, 21(7):827-851.
  HE J, CHEN WQ, LI ZS, et al. China guideline for the screening, early detection and early treatment of gastric cancer (2022, Beijing)[J]. Chin J Dig Surg, 2022, 21(7):827-851.
[44] TAO E W, WANG H L, CHENG W Y, et al. A specific tRNA half, 5'tiRNA-His-GTG, responds to hypoxia via the HIF1α/ANG axis and promotes colorectal cancer progression by regulating LATS2[J]. J Exp Clin Cancer Res, 2021, 40(1):67.
[45] LUAN N, MU Y, MU J, et al. Dicer1 promotes colon cancer cell invasion and migration through modulation of tRF-20-MEJB5Y13 expression under hypoxia[J]. Front Genet, 2021, 12:638244.
[46] LU S, WEI X, TAO L, et al. A novel tRNA-derived fragment tRF-3022b modulates cell apoptosis and M2 macrophage polarization via binding to cytokines in colorectal cancer[J]. J Hematol Oncol, 2022, 15(1):176.
[47] SHEN Y, XIE Y, YU X, et al. Clinical diagnostic values of transfer RNA-derived fragment tRF-19-3L7L73JD and its effects on the growth of gastric cancer cells[J]. J Cancer, 2021, 12(11):3230-3238.
[48] DONG X, FAN X, HE X, et al. Comprehensively identifying the key trna-derived fragments and investigating their function in gastric cancer processes[J]. Onco Targets Ther, 2020, 13:10931-10943.
[49] ZHU L, LI Z, YU X, et al. The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway[J]. Stem Cell Res Ther, 2021, 12(1):418.
[50] CUI H, LI H, WU H, et al. A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer[J]. Cell Death Dis, 2022, 13(5):471.
[51] MO D, JIANG P, YANG Y, et al. A tRNA fragment, 5'-tiRNAVal, suppresses the Wnt/β-catenin signaling pathway by targeting FZD3 in breast cancer[J]. Cancer Lett, 2019, 457:60-73.
[52] SHAN N, LI N, DAI Q, et al. Interplay of tRNA-derived fragments and T cell activation in breast cancer patient survival[J]. Cancers (Basel), 2020, 12(8):2230.
[53] LI J, ZHU L, CHENG J, et al. Transfer RNA-derived small RNA: A rising star in oncology[J]. Semin Cancer Biol, 2021, 75:29-37.
[54] WU Y, YANG X, JIANG G, et al. 5'-tRF-GlyGCC: a tRNA-derived small RNA as a novel biomarker for colorectal cancer diagnosis[J]. Genome Med, 2021, 13(1):20.
[55] ZHU L, LI T, SHEN Y, et al. Using tRNA halves as novel biomarkers for the diagnosis of gastric cancer[J]. Cancer Biomark, 2019, 25(2):169-176.
[56] SHEN Y, YU X, RUAN Y, et al. Global profile of tRNA-derived small RNAs in gastric cancer patient plasma and identification of tRF-33-P4R8YP9LON4VDP as a new tumor suppressor[J]. Int J Med Sci, 2021, 18(7):1570-1579.
[57] WANG J, MA G, GE H, et al. Circulating tRNA-derived small RNAs (tsRNAs) signature for the diagnosis and prognosis of breast cancer[J]. NPJ Breast Cancer, 2021, 7(1):4.
[58] ZHANG Y, GU X, QIN X, et al. Evaluation of serum tRF-23-Q99P9P9NDD as a potential biomarker for the clinical diagnosis of gastric cancer[J]. Mol Med, 2022, 28(1):63.
[59] LI Y, ZHANG Y, LI X, et al. Serum tRF-27-FDXXE6XRK45 as a promising biomarker for the clinical diagnosis in gastric cancer[J]. Int J Med Sci, 2023, 20(9):1189-1201.
[60] LI X, ZHANG Y, LI Y, et al. A comprehensive evaluation of serum tRF-29-R9J8909NF5JP as a novel diagnostic and prognostic biomarker for gastric cancer[J]. Mol Carcinog, 2023, 62(10):1504-1517.
[61] FENG W, LI Y, CHU J, et al. Identification of tRNA-derived small noncoding RNAs as potential biomarkers for prediction of recurrence in triple-negative breast cancer[J]. Cancer Med, 2018, 7(10):5130-5144.
[62] HUANG Y, GE H, ZHENG M, et al. Serum tRNA-derived fragments (tRFs) as potential candidates for diagnosis of nontriple negative breast cancer[J]. J Cell Physiol, 2020, 235(3):2809-2824.
[63] MO D, HE F, ZHENG J, et al. tRNA-derived fragment tRF-17-79MP9PP Attenuates Cell Invasion and migration via THBS1/TGF-β1/Smad3 axis in breast cancer[J]. Front Oncol, 2021, 11:656078.
[64] ZHAN S, YANG P, ZHOU S, et al. Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis. Front Med. 2022; 16(2):216-226.
[65] LIN C, ZHENG L, HUANG R, et al. tRFs as potential exosome tRNA-derived fragment biomarkers for gastric carcinoma[J]. Clin Lab, 2020, 66(6):10.7754/Clin.Lab.2019.190811.
[66] ZHU L, LI J, GONG Y, et al. Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis[J]. Mol Cancer, 2019, 18(1):74.
[67] LI K, LIN Y, LUO Y, et al. A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study[J]. Mol Cancer, 2022, 21(1):21.
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