转运RNA衍生小RNA（tsRNA）的生物学功能及在肝脏疾病中的表达和临床意义

李银丽; 徐炎; 管志伟; 孟璐; 渠怡彤; 邱建利

doi:10.12449/JCH250634

转运RNA衍生小RNA（tsRNA）的生物学功能及在肝脏疾病中的表达和临床意义

DOI: 10.12449/JCH250634

李银丽^{1, 2},
徐炎^{1, 2},
管志伟^{1, 2},
孟璐^{1, 2},
渠怡彤^{1, 2},
邱建利^{1, 2, , ,}

1.
河南中医药大学第一附属医院儿科医院，郑州 450000
2.
河南中医药大学儿科医学院，郑州 450000

基金项目:

国家自然科学基金 (81804142);

国家自然科学基金 (82474570);

中国博士后科学基金面上项目 (2023M731027)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李银丽负责论文资料收集与总结，撰写论文；徐炎、管志伟负责论文审阅与修订；孟璐、渠怡彤参与论文资料收集与整理；邱建利负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
邱建利， qiujianli@126.com （ORCID： 0000-0001-6796-3774）

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出版历程
- 收稿日期: 2024-09-29
- 录用日期: 2024-11-07
- 出版日期: 2025-06-25

Biological function of tRNA-derived small RNA and its expression and clinical significance in liver diseases

Yinli LI^{1, 2},
Yan XU^{1, 2},
Zhiwei GUAN^{1, 2},
Lu MENG^{1, 2},
Yitong QU^{1, 2},
Jianli QIU^{1, 2
, ,
,}

1.
Children’s Hospital，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China
2.
School of Pediatrics，Henan University of Chinese Medicine，Zhengzhou 450000，China

Research funding:

National Natural Science Foundation of China (81804142);

National Natural Science Foundation of China (82474570);

China Postdoctoral Science Foundation General Program (2023M731027)

More Information

Corresponding author: QIU Jianli， qiujianli@126.com （ORCID： 0000-0001-6796-3774）

摘要

摘要: 肝脏疾病早期不易被发现，有创性诊断方式如肝穿刺虽然诊断相对准确，但接受度不高，严重制约肝脏疾病诊疗技术的提高，因此寻找新的生物标志物及新的治疗靶点尤为重要。转运RNA衍生小RNA（tsRNA）作为新兴的液体活检生物标志物，在病毒性肝炎、脂肪性肝病、肝损伤、肝癌等肝脏疾病中异常表达，通过发挥调节基因表达、表观遗传调控、蛋白质翻译等生物学功能，影响肝脏疾病的发生和进展。本文就tsRNA的来源和分类、生物学功能以及tsRNA作为肝脏疾病生物标志物和潜在治疗靶点进行综述，以期为肝脏疾病的早期诊断及治疗提供思路。
- 微RNAs /
- 肝疾病 /
- 生物标记
Abstract: Liver diseases cannot be easily detected in the early stage， and although invasive diagnostic methods， such as liver biopsy， are relatively accurate， they tend to have a low degree of acceptance， which greatly limits the improvement in diagnosis and treatment techniques for liver diseases. Therefore， it is of great importance to search for new biomarkers and therapeutic targets. As an emerging biomarker for liquid biopsy， tRNA-derived small RNA （tsRNA） is abnormally expressed in various liver diseases including viral hepatitis， fatty liver disease， liver injury， and liver cancer， and it can affect the development and progression of liver diseases by regulating the biological functions such as gene expression， epigenetic regulation， and protein translation. This article reviews the origin， classification， and biological function of tsRNA， as well as the research advances in tsRNA as biomarkers and potential therapeutic targets for liver diseases， so as to provide ideas for the early diagnosis and treatment of liver diseases.
- MicroRNAs /
- Liver Diseases /
- Biomarkers

HTML全文

图 1 tsRNA影响基因甲基化

Figure 1. tsRNA affects gene methylation

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图 2 tsRNA参与转录后基因沉默

Figure 2. tsRNA is involved in post-transcriptional silencing of genes

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图 3 tsRNA影响mRNA的稳定性

Figure 3. tsRNA influences the stability of mRNA

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图 4 tsRNA阻碍翻译起始

Figure 4. tsRNA hinders translation initiation

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图 5 tsRNA影响核糖体生物发生

Figure 5. tsRNA affects ribosome biogenesis

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图 6 tsRNA抑制细胞凋亡

Figure 6. tsRNA inhibits apoptosis

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表 1 tsRNA的类型

Table 1. Types of tsRNA

tsRNA	亚型	生成机制	长度	位置
tRF	tRF-1	由核糖核酸酶Z剪切前体tRNA的3'端产生	14～30 nt	细胞质
	tRF-2	机制不明		不清楚
	tRF-3	由成熟tRNA 3'端T-环处经核酸内切酶切割产生		细胞质
	tRF-5	由成熟tRNA 5'端的D-环或D-环和反密码子环之间的区域通过Dicer酶切割产生		细胞核
	i-tRF	机制不明		不清楚
tiRNA	3'tiRNA	由成熟tRNA反密码子环经ANG特异性切割产生	31～40 nt	细胞质
	5'tiRNA		31～40 nt	细胞质
	tRNA-3		>40 nt	不清楚
	tRNA-5		>40 nt	不清楚

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表 2 tsRNA在肝脏疾病中的表达及临床意义

Table 2. The expression of tsRNA in liver diseases and its clinical significance

疾病	tsRNA	所属亚类	表达	临床意义
ALD	Gly-tRF	tRF	上调	促进肝损伤和脂肪变性，ALD的潜在治疗靶点^［38］
MAFLD	tRF-Val-CAC-005 tRF-Ala-CGC-006 tiRNA-His-GTG-001	tRF-5b tRF-5c tiRNA-5	上调	用于MAFLD诊断及肝纤维化预测^［40］
	tRF-3001b	tRF	上调	抑制自噬相关基因Prkaa1的表达，促进MAFLD的发展，MAFLD的潜在治疗靶点^［41］
	tRF-47	tRF	‒	激活自噬，减少肝脂质形成，MAFLD的潜在治疗靶点^［42］
HCC	tRNA-val tac-3 tRNA-GlyTCC-5 tRNA-ValAAC-5 tRNA-GluCTC-5	tRF-3 5'tiRNA 5'tiRNA tRF-5	上调	用于HCC临床诊断^［45］
	tRF-40-EFOK8YR951K36D26 tRF-34-QNR8VP94FQFY1Q tRF-32-79mp9NH57SJ tRF-31-87R8WP9N1EWJ0	tRF	上调	用于HCC临床诊断^［46］
	tRF-Gln-TTG-006	tRF-5	上调	用于HCC临床诊断^［47］
	ts-N22	‒	‒	调节肿瘤抑制因子hsa-miR-33a表达，改善HCC的不良预后，调节 miR-33a-5p干扰HCC细胞对顺铂的耐药性，用于HCC预后判断^［44］
	tRF-39-8HM2OSRNLKSEKH9	tRF	上调	与肿瘤大小呈正相关，其过表达可加速细胞迁移能力，用于HCC 预后判断^［48］
	Gly-tRF	tRF	上调	负调节NDFIP2和激活AKT信号通路，促进肝癌恶化和转移，HCC 的潜在治疗靶点^［49］
	LeuCAG3'tsRNA	tRF	‒	LeuCAG3'tsRNA的抑制可诱导癌细胞凋亡，HCC的潜在治疗靶点^［50］
	5'-tiRNA-Gln	5'tiRNA	‒	抑制相关信号通路阻止HCC进展，HCC的潜在治疗靶点^［25］
ACLF	tsRNA-20、tsRNA-46	‒	上调	用于ACLF早期诊断^［52］
ACLF	tRF-Gln-CTG-026	tRF-1	‒	促进肝脏修复，ACLF的潜在治疗靶点^［53］
HBV/HCV	5'tRH Val 5'tRH Gly	5'tiRNA	上调	用于HBV/HCV临床诊断^［54］
注：“‒”表示不明确。

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参考文献(54)

[1]	SARIN SK, KUMAR M, ESLAM M, et al. Liver diseases in the Asia-Pacific Region: A Lancet Gastroenterology& Hepatology Commission[J]. Lancet Gastroenterol Hepatol, 2020, 5( 2): 167- 228. DOI: 10.1016/S2468-1253(19)30342-5.
[2]	LIU ZQ, LIN CQ, MAO XH, et al. Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: A systematic literature review and meta-analysis of 3 740 studies and 231 million people[J]. Gut, 2023, 72( 12): 2354- 2363. DOI: 10.1136/gutjnl-2023-330691.
[3]	ZHOU JH, ZHOU F, WANG WX, et al. Epidemiological features of NAFLD from 1999 to 2018 in China[J]. Hepatology, 2020, 71( 5): 1851- 1864. DOI: 10.1002/hep.31150.
[4]	YANG B, ZHANG R. Progress on the treatment of metabolic associated fatty liver disease[J/CD]. Chin J Liver Dis(Electronic Edition), 2024, 16( 4): 25- 30. DOI: 10.3969/j.issn.1674-7380.2024.04.00. 杨彬, 张瑞. 代谢相关脂肪性肝病治疗进展[J/CD]. 中国肝脏病杂志(电子版), 2024, 16( 4): 25- 30. DOI: 10.3969/j.issn.1674-7380.2024.04.00.
[5]	ZHANG F, JU JM, DIAO HT, et al. Innovative pharmacotherapy for hepatic metabolic and chronic inflammatory diseases in China[J]. Br J Pharmacol, 2024. DOI: 10.1111/bph.16342.[ Online ahead of print]
[6]	TSONEVA DK, IVANOV MN, VINCIGUERRA M. Liquid liver biopsy for disease diagnosis and prognosis[J]. J Clin Transl Hepatol, 2023, 11( 7): 1520- 1541. DOI: 10.14218/jcth.2023.00040.
[7]	DU J, HUANG TY, ZHENG Z, et al. Biological function and clinical application prospect of tsRNAs in digestive system biology and pathology[J]. Cell Commun Signal, 2023, 21( 1): 302. DOI: 10.1186/s12964-023-01341-8.
[8]	XIE YY, YAO LP, YU XC, et al. Action mechanisms and research methods of tRNA-derived small RNAs[J]. Signal Transduct Target Ther, 2020, 5( 1): 109. DOI: 10.1038/s41392-020-00217-4.
[9]	KATSARAKI K, ARTEMAKI PI, PAPAGEORGIOU SG, 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. DOI: 10.1016/j.leukres.2019.106234.
[10]	PENG RF, SANTOS HJ, NOZAKI T. Transfer RNA-derived small RNAs in the pathogenesis of parasitic protozoa[J]. Genes(Basel), 2022, 13( 2): 286. DOI: 10.3390/genes13020286.
[11]	YU XC, XIE YY, ZHANG SS, et al. tRNA-derived fragments: Mechanisms underlying their regulation of gene expression and potential applications as therapeutic targets in cancers and virus infections[J]. Theranostics, 2021, 11( 1): 461- 469. DOI: 10.7150/thno.51963.
[12]	YANG N, LI RJ, LIU RA, et al. The emerging function and promise of tRNA-derived small RNAs in cancer[J]. J Cancer, 2024, 15( 6): 1642- 1656. DOI: 10.7150/jca.89219.
[13]	LIAO JY, GUO YH, ZHENG LL, et al. Both endo-siRNAs and tRNA-derived small RNAs are involved in the differentiation of primitive eukaryote Giardia Lamblia[J]. Proc Natl Acad Sci U S A, 2014, 111( 39): 14159- 14164. DOI: 10.1073/pnas.1414394111.
[14]	BALATTI V, NIGITA G, VENEZIANO D, et al. tsRNA signatures in cancer[J]. Proc Natl Acad Sci U S A, 2017, 114( 30): 8071- 8076. DOI: 10.1073/pnas.1706908114.
[15]	ZHANG X, HE X, LIU C, et al. IL-4 inhibits the biogenesis of an epigenetically suppressive PIWI-interacting RNA to upregulate CD1a molecules on monocytes/dendritic cells[J]. J Immunol, 2016, 196( 4): 1591- 1603. DOI: 10.4049/jimmunol.1500805.
[16]	TONG LH, ZHANG WX, QU BC, et al. The tRNA-derived fragment-3017A promotes metastasis by inhibiting NELL2 in human gastric cancer[J]. Front Oncol, 2021, 10: 570916. DOI: 10.3389/fonc.2020.570916.
[17]	ZHANG SS, GU YQ, GE JX, et al. tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner[J]. Oncogene, 2024, 43( 28): 2160- 2171. DOI: 10.1038/s41388-024-03062-9.
[18]	GOODARZI H, LIU XH, NGUYEN HCB, et al. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement[J]. Cell, 2015, 161( 4): 790- 802. DOI: 10.1016/j.cell.2015.02.053.
[19]	FALCONI M, GIANGROSSI M, ZABALETA ME, et al. A novel 3'- tRNA^Glu-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin[J]. FASEB J, 2019, 33( 12): 13228- 13240. DOI: 10.1096/fj.201900382rr.
[20]	CHEN Q, YAN MH, CAO ZH, et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder[J]. Science, 2016, 351( 6271): 397- 400. DOI: 10.1126/science.aad7977.
[21]	SARKER G, SUN WF, ROSENKRANZ D, et al. Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs[J]. Proc Natl Acad Sci USA, 2019, 116( 21): 10547- 10556. DOI: 10.1073/pnas.1820810116.
[22]	ZHANG YF, ZHANG XD, SHI JC, et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs[J]. Nat Cell Biol, 2018, 20( 5): 535- 540. DOI: 10.1038/s41556-018-0087-2.
[23]	YU T, XIE YM, TANG C, et al. Dnmt2-null sperm block maternal transmission of a paramutant phenotype[J]. Biol Reprod, 2021, 105( 3): 603- 612. DOI: 10.1093/biolre/ioab086.
[24]	SHI JC, ZHANG YF, ZHOU T, et al. tsRNAs: The Swiss army knife for translational regulation[J]. Trends Biochem Sci, 2019, 44( 3): 185- 189. DOI: 10.1016/j.tibs.2018.09.007.
[25]	WU CD, LIU DK, ZHANG LF, et al. 5'-tiRNA-Gln inhibits hepatocellular carcinoma progression by repressing translation through the interaction with eukaryotic initiation factor 4A-I[J]. Front Med, 2023, 17( 3): 476- 492. DOI: 10.1007/s11684-022-0966-6.
[26]	GEBETSBERGER J, WYSS L, MLECZKO AM, 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. DOI: 10.1080/15476286.2016.1257470.
[27]	MLECZKO AM, CELICHOWSKI P, BĄKOWSKA-ŻYWICKA K. Transfer RNA-derived fragments target and regulate ribosome-associated aminoacyl-transfer RNA synthetases[J]. Biochim Biophys Acta Gene Regul Mech, 2018: S1874-9399(17)30380- 2. DOI: 10.1016/j.bbagrm.2018.06.001.
[28]	FRICKER R, BROGLI R, LUIDALEPP H, et al. A tRNA half modulates translation as stress response in Trypanosoma brucei[J]. Nat Commun, 2019, 10( 1): 118. DOI: 10.1038/s41467-018-07949-6.
[29]	KIM HK, XU JP, 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. DOI: 10.1016/j.celrep.2019.11.062.
[30]	SAIKIA M, JOBAVA R, PARISIEN M, et al. Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress[J]. Mol Cell Biol, 2014, 34( 13): 2450- 2463. DOI: 10.1128/MCB.00136-14.
[31]	KEAM SP, SOBALA A, HAVE S TEN, et al. tRNA-derived RNA fragments associate with human multisynthetase complex(MSC) and modulate ribosomal protein translation[J]. J Proteome Res, 2017, 16( 2): 413- 420. DOI: 10.1021/acs.jproteome.6b00267.
[32]	DI FAZIO A, GULLEROVA M. An old friend with a new face: tRNA-derived small RNAs with big regulatory potential in cancer biology[J]. Br J Cancer, 2023, 128( 9): 1625- 1635. DOI: 10.1038/s41416-023-02191-4.
[33]	BRAICU C, ZIMTA AA, HARANGUS A, et al. The function of non-coding RNAs in lung cancer tumorigenesis[J]. Cancers(Basel), 2019, 11( 5): 605. DOI: 10.3390/cancers11050605.
[34]	SHI JC, ZHANG YF, TAN DM, et al. PANDORA-seq expands the repertoire of regulatory small RNAs by overcoming RNA modifications[J]. Nat Cell Biol, 2021, 23( 4): 424- 436. DOI: 10.1038/s41556-021-00652-7.
[35]	RUZMAN L, MIKOLASEVIC I, BARABA DEKANIC K, et al. Advances in diagnosis of chronic liver diseases in pediatric patients[J]. World J Pediatr, 2018, 14( 6): 541- 547. DOI: 10.1007/s12519-018-0197-8.
[36]	SINGH S, OSNA NA, KHARBANDA KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review[J]. World J Gastroenterol, 2017, 23( 36): 6549- 6570. DOI: 10.3748/wjg.v23.i36.6549.
[37]	ZHANG PY, WANG WY, MAO M, et al. Similarities and differences: A comparative review of the molecular mechanisms and effectors of NAFLD and AFLD[J]. Front Physiol, 2021, 12: 710285. DOI: 10.3389/fphys.2021.710285.
[38]	ZHONG FD, HU ZG, JIANG KQ, et al. Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis[J]. Cell Res, 2019, 29( 7): 548- 561. DOI: 10.1038/s41422-019-0175-2.
[39]	HUANG P, TU B, LIAO HJ, et al. Elevation of plasma tRNA fragments as a promising biomarker for liver fibrosis in nonalcoholic fatty liver disease[J]. Sci Rep, 2021, 11( 1): 5886. DOI: 10.1038/s41598-021-85421-0.
[40]	KIM Y, LEE DH, PARK SH, et al. The interplay of microRNAs and transcription factors in autophagy regulation in nonalcoholic fatty liver disease[J]. Exp Mol Med, 2021, 53( 4): 548- 559. DOI: 10.1038/s12276-021-00611-0.
[41]	ZHU JJ, CHENG ML, ZHAO XK. A tRNA-derived fragment(tRF-3001b) aggravates the development of nonalcoholic fatty liver disease by inhibiting autophagy[J]. Life Sci, 2020, 257: 118125. DOI: 10.1016/j.lfs.2020.118125.
[42]	ZHU JJ, WEN Y, ZHANG QL, et al. The monomer TEC of blueberry improves NASH by augmenting tRF-47-mediated autophagy/pyroptosis signaling pathway[J]. J Transl Med, 2022, 20( 1): 128. DOI: 10.1186/s12967-022-03343-5.
[43]	ANWANWAN D, SINGH SK, SINGH S, et al. Challenges in liver cancer and possible treatment approaches[J]. Biochim Biophys Acta Rev Cancer, 2020, 1873( 1): 188314. DOI: 10.1016/j.bbcan.2019.188314.
[44]	ZUO Y, CHEN SQ, YAN LL, et al. Development of a tRNA-derived small RNA diagnostic and prognostic signature in liver cancer[J]. Genes Dis, 2021, 9( 2): 393- 400. DOI: 10.1016/j.gendis.2021.01.006.
[45]	ZHU L, LI J, GONG YL, et al. Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis[J]. Mol Cancer, 2019, 18( 1): 74. DOI: 10.1186/s12943-019-1000-8.
[46]	WANG Y, WENG QY, GE JX, et al. tRNA-derived small RNAs: Mechanisms and potential roles in cancers[J]. Genes Dis, 2022, 9( 6): 1431- 1442. DOI: 10.1016/j.gendis.2021.12.009.
[47]	ZHAN SB, YANG P, ZHOU SK, et al. Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis[J]. Front Med, 2022, 16( 2): 216- 226. DOI: 10.1007/s11684-022-0920-7.
[48]	XU TX, YUAN J, SONG F, et al. Exploring the functional role of tRF-39-8HM2OSRNLNKSEKH9 in hepatocellular carcinoma[J]. Heliyon, 2024, 10( 5): e27153. DOI: 10.1016/j.heliyon.2024.e27153.
[49]	ZHOU YQ, HU JJ, LIU L, et al. Gly-tRF enhances LCSC-like properties and promotes HCC cells migration by targeting NDFIP2[J]. Cancer Cell Int, 2021, 21( 1): 502. DOI: 10.1186/s12935-021-02102-8.
[50]	KIM HK, FUCHS G, WANG SC, et al. A transfer-RNA-derived small RNA regulates ribosome biogenesis[J]. Nature, 2017, 552( 7683): 57- 62. DOI: 10.1038/nature25005.
[51]	LUO JJ, LI JQ, LI P, et al. Acute-on-chronic liver failure: Far to go-a review[J]. Crit Care, 2023, 27( 1): 259. DOI: 10.1186/s13054-023-04540-4.
[52]	XU WL, YU MX, WU YK, et al. Plasma-derived exosomal sncRNA as a promising diagnostic biomarker for early detection of HBV-related acute-on-chronic liver failure[J]. Front Cell Infect Microbiol, 2022, 12: 923300. DOI: 10.3389/fcimb.2022.923300.
[53]	YING SY, LI PC, WANG JQ, et al. tRF-Gln-CTG-026 ameliorates liver injury by alleviating global protein synthesis[J]. Signal Transduct Target Ther, 2023, 8( 1): 144. DOI: 10.1038/s41392-023-01351-5.
[54]	SELITSKY SR, BARAN-GALE J, HONDA M, et al. Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C[J]. Sci Rep, 2015, 5: 7675. DOI: 10.1038/srep07675.