Small non-coding RNAs (sncRNAs) play critical roles in multiple regulatory processes, including transcription, post-transcription, and translation. Emerging evidence reveals the critical roles of sncRNAs in cancer development and their potential role as biomarkers and/or therapeutic targets. In this paper, we review recent research on four sncRNA species with functional significance in cancer: small nucleolar RNAs, transfer RNA, small nuclear RNAs, and piwi-interacting RNAs. We introduce their functional roles in tumorigenesis and discuss the potential utility of sncRNAs as prognostic and diagnostic biomarkers and therapeutic targets. We further summarize approaches to characterize sncRNAs in a high-throughput manner, including the specific library construction and computational framework. Our review provides a perspective of the functions, clinical utility, and characterization of sncRNAs in cancer.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Romano G, Veneziano D, Acunzo M, Croce CM. Small non-coding RNA and cancer. Carcinogenesis. 2017;38:485–91.
Wong CM, Tsang FH, Ng IOL. Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol. 2018;15:137–51.
Peng Y, Croce CM. The role of microRNAs in human cancer. Signal Transduct Target Ther. 2016;1. https://doi.org/10.1038/sigtrans.2015.4.
Olson P, Lu J, Zhang H, Shai A, Chun MG, Wang Y, et al. MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev. 2009;23:2152–65.
Zheng T, Wang J, Chen X, Liu L. Role of microRNA in anticancer drug resistance. Int J Cancer. 2010;126:2–10.
Grady WM, Tewari M. The next thing in prognostic molecular markers: microRNA signatures of cancer. Gut. 2010;59:706–8.
Paranjape T, Slack FJ, Weidhaas JB. MicroRNAs: tools for cancer diagnostics. Gut. 2009;58:1546–54.
Weinstein JN, Collisson EA, Mills GB, Shaw KRM, Ozenberger BA, Ellrott K, et al. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45:1113–20.
Ghandi M, Huang FW, Jané-Valbuena J, Kryukov GV, Lo CC, McDonald ER, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569:503–8.
Vickers KC, Roteta LA, Hucheson-Dilks H, Han L, Guo Y. Mining diverse small RNA species in the deep transcriptome. Trends Biochem Sci. 2015;40:4–7.
Jorjani H, Kehr S, Jedlinski DJ, Gumienny R, Hertel J, Stadler PF, et al. An updated human snoRNAome. Nucleic Acids Res. 2016;44:5068–82.
Dupuis-Sandoval F, Poirier M, Scott MS. The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdiscip Rev RNA. 2015;6:381–97.
Zhou F, Liu Y, Rohde C, Pauli C, Gerloff D, Köhn M, et al. AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia. Nat Cell Biol. 2017;19:844–55.
Kiss T, Fayet-Lebaron E, Jády BE. Box H/ACA small ribonucleoproteins. Mol Cell. 2010;37:597–606.
Bachellerie JP, Cavaillé J, Hüttenhofer A. The expanding snoRNA world. Biochimie. 2002;84:775–90.
Liang J, Wen J, Huang Z, Chen X, Zhang B, Chu L. Small nucleolar RNAs: insight into their function in cancer. Front Oncol. 2019;9. https://doi.org/10.3389/fonc.2019.00587.
Fang X, Yang D, Luo H, Wu S, Dong W, Xiao J, et al. SNORD126 promotes HCC and CRC cell growth by activating the PI3K-AKT pathway through FGFR2. J Mol Cell Biol. 2017;9:243–55.
Siprashvili Z, Webster DE, Johnston D, Shenoy RM, Ungewickell AJ, Bhaduri A, et al. The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. Nat Genet. 2015;48:53–58.
Su H, Xu T, Ganapathy S, Shadfan M, Long M, Huang THM, et al. Elevated snoRNA biogenesis is essential in breast cancer. Oncogene. 2014;33:1348–58.
Cao P, Yang A, Wang R, Xia X, Zhai Y, Li Y, et al. Germline duplication of SNORA18L5 increases risk for HBV-related hepatocellular carcinoma by altering localization of ribosomal proteins and decreasing levels of p53. Gastroenterology. 2018;155:542–56.
Mannoor K, Shen J, Liao J, Liu Z, Jiang F. Small nucleolar RNA signatures of lung tumor-initiating cells. Mol Cancer. 2014;13:1–12.
Yang Y, Zhang H, Xie Y, Zhang S, Zhu J, Yin G, et al. Preliminary screening and identification of differentially expressed metastasis-related ncRNAs in ovarian cancer. Oncol Lett. 2018;15:368–74.
Cui L, Nakano K, Obchoei S, Setoguchi K, Matsumoto M, Yamamoto T, et al. Small nucleolar noncoding RNA SNORA23, up-regulated in human pancreatic ductal adenocarcinoma, regulates expression of spectrin repeat-containing nuclear envelope 2 to promote growth and metastasis of xenograft tumors in mice. Gastroenterology. 2017;153:292–306. e2.
Gong J, Li Y, Liu C, Xiang Y, Li C, Ye Y, et al. A pan-cancer analysis of the expression and clinical relevance of small nucleolar RNAs in human cancer. Cell Rep. 2017;21:1968–81.
Xiang Y, Ye Y, Zhang Z, Han L. Maximizing the utility of cancer transcriptomic data. Trends Cancer. 2018;4:823–37.
Zheng D, Zhang J, Ni J, Luo J, Wang J, Tang L, et al. Small nucleolar RNA 78 promotes the tumorigenesis in non-small cell lung cancer. J Exp Clin Cancer Res. 2015;34. https://doi.org/10.1186/s13046-015-0170-5.
Gao L, Ma J, Mannoor K, Guarnera MA, Shetty A, Zhan M, et al. Genome-wide small nucleolar RNA expression analysis of lung cancer by next-generation deep sequencing. Int J Cancer. 2015;136:E623–9.
Liu Y, Ruan H, Li S, Ye Y, Hong W, Gong J, et al. The genetic and pharmacogenomic landscape of snoRNAs in human cancer. Mol Cancer. 2020;19. https://doi.org/10.1186/s12943-020-01228-z.
Chan PP, Lowe TM. GtRNAdb 2.0: an expanded database of transfer RNA genes identified in complete and draft genomes. Nucleic Acids Res. 2016;44:D184–9.
Dever TE, Green R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol. 2012;4:1–16.
Grewal SS. Why should cancer biologists care about tRNAs? tRNA synthesis, mRNA translation and the control of growth. Biochim Biophys Acta. 2015;1849:898–907.
Gomez-Roman N, Grandori C, Eisenman RN, White RJ. Direct activation of RNA polymerase III transcription by c-Myc. Nature. 2003;421:290–4.
Felton-Edkins ZA, Fairley JA, Graham EL, Johnston IM, White RJ, Scott PH. The mitogen-activated protein (MAP) kinase ERK induces tRNA synthesis by phosphorylating TFIIIB. EMBO J. 2003;22:2422–32.
Kassavetis GA, Letts GA, Geiduschek EP. The RNA polymerase III transcription initiation factor TFIIIB participates in two steps of promoter opening. EMBO J. 2001;20:2823–34.
Zhang Z, Ye Y, Gong J, Ruan H, Liu CJ, Xiang Y, et al. Global analysis of tRNA and translation factor expression reveals a dynamic landscape of translational regulation in human cancers. Commun Biol. 2018;1. https://doi.org/10.1038/s42003-018-0239-8.
Goodarzi H, Nguyen HCB, Zhang S, Dill BD, Molina H, Tavazoie SF. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell. 2016;165:1416–27.
Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner MR, Pan T. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009;37:7268–80.
Hernandez‐Alias X, Benisty H, Schaefer MH, Serrano L. Translational efficiency across healthy and tumor tissues is proliferation‐related. Mol Syst Biol. 2020;16. https://doi.org/10.15252/msb.20199275.
Zhang Z, Ruan H, Liu CJ, Ye Y, Gong J, Diao L, et al. tRic: a user-friendly data portal to explore the expression landscape of tRNAs in human cancers. RNA Biol. 2019. https://doi.org/10.1080/15476286.2019.1657744.
Clarke CJ, Berg TJ, Birch J, Ennis D, Mitchell L, Cloix C, et al. The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol. 2016;26:755–65.
Santos M, Fidalgo A, Varanda AS, Oliveira C, Santos MAS. tRNA deregulation and its consequences in cancer. Trends Mol Med. 2019;25:853–65.
Wang X, Chow CR, Ebine K, Lee J, Rosner MR, Pan T, et al. Interaction of tRNA with MEK2 in pancreatic cancer cells. Sci Rep. 2016;6. https://doi.org/10.1038/srep28260.
Pan T. Modifications and functional genomics of human transfer RNA. Cell Res. 2018;28:395–404.
Erber L, Hoffmann A, Fallmann J, Betat H, Stadler PF, Mörl M. LOTTE-seq (Long hairpin oligonucleotide based tRNA high-throughput sequencing): specific selection of tRNAs with 3’-CCA end for high-throughput sequencing. RNA Biol. 2020;17:23–32.
Shigematsu M, Honda S, Loher P, Telonis AG, Rigoutsos I, Kirino Y. YAMAT-seq: an efficient method for high-throughput sequencing of mature transfer RNAs. Nucleic Acids Res. 2017;45:e70.
Zheng G, Qin Y, Clark WC, Dai Q, Yi C, He C, et al. Efficient and quantitative high-throughput tRNA sequencing. Nat Methods. 2015;12:835–7.
Hoffmann A, Fallmann J, Vilardo E, Mörl M, Stadler PF, Amman F. Accurate mapping of tRNA reads. Bioinformatics. 2018;34:1116–24.
Vinson V. Structure and function of the spliceosome. Science (80-). 2015;349:1178.3–1178.
Chen W, Moore MJ. Spliceosomes. Curr Biol. 2015;25:R181–3.
Kosmyna B, Gupta V, Query C. Transcriptional analysis supports the expression of human snRNA variants and reveals U2 snRNA homeostasis by an abundant U2 variant. bioRxiv. 2020. https://doi.org/10.1101/2020.01.24.917260.
Warashina M, Kuwabara T, Kawasaki H, et al. RNA in biotechnology: towards a role for ribozymes in gene therapy. RNA. 2001;13:277–308.
Beggs JD. Lsm proteins and RNA processing. Biochem Soc Trans. 2005;33:433–8.
Dvinge H, Guenthoer J, Porter PL, Bradley RK. RNA components of the spliceosome regulate tissue and cancer-specific alternative splicing. Genome Res. 2019;29:1591–604.
Cheng Z, Sun Y, Niu X, Shang Y, Ruan J, Chen Z, et al. Gene expression profiling reveals U1 snRNA regulates cancer gene expression. Oncotarget. 2017;8:112867–74.
Shuai S, Suzuki H, Diaz-Navarro A, Nadeu F, Kumar SA, Gutierrez-Fernandez A, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature. 2019;574:712–6.
Suzuki Hiromichi, Kumar SachinA, Shuai Shimin, Diaz-Navarro Ander, Gutierrez-Fernandez Ana, De Antonellis Pasqualino, et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019;574:707–11.
Inoue D, Guo-Liang C, Liu B, Lee SC, Michel BC, Pangallo J. et al. Spliceosomal disruption of the non-canonical SWI/SNF chromatin remodeling complex in SF3B1 mutant leukemias. Blood. 2019;134:637.
Dong X, Ding S, Yu M, Niu L, Xue L, Zhao Y, et al. Small nuclear RNAs (U1, U2, U5) in tumor-educated platelets are downregulated and act as promising biomarkers in lung cancer. Front Oncol. 2020;10. https://doi.org/10.3389/fonc.2020.01627.
Oh JM, Venters CC, Di C, Pinto AM, Wan L, Younis I, et al. U1 snRNP regulates cancer cell migration and invasion in vitro. Nat Commun. 2020;11. https://doi.org/10.1038/s41467-019-13993-7.
Isakova A, Fehlmann T, Keller A, Quake SR. A mouse tissue atlas of small noncoding RNA. Proc Natl Acad Sci USA. 2020;117:25634–45.
Chu A, Robertson G, Brooks D, Mungall AJ, Birol I, Coope R, et al. Large-scale profiling of microRNAs for the cancer genome atlas. Nucleic Acids Res. 2016;44:e3.
Murillo OD, Thistlethwaite W, Rozowsky J, Subramanian SL, Lucero R, Shah N. et al. exRNA atlas analysis reveals distinct extracellular RNA cargo types and their carriers present across human biofluids. Cell. 2019;177:463–77.e15.
Liu Y, Dou M, Song X, Dong Y, Liu S, Liu H. et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer. 2019;18:1–15. https://doi.org/10.1186/s12943-019-1052-9.
Moyano M, Stefani G. PiRNA involvement in genome stability and human cancer. J Hematol Oncol. 2015;8. https://doi.org/10.1186/s13045-015-0133-5.
Girard A, Sachidanandam R, Hannon GJ, Carmell MA. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature. 2006;442:199–202.
Chalbatani GM, Dana H, Memari F, Gharagozlou E, Ashjaei S, Kheirandish P, et al. Biological function and molecular mechanism of piRNA in cancer. Pract Lab Med. 2019;13. https://doi.org/10.1016/j.plabm.2018.e00113.
Cheng J, Guo JM, Xiao BX, Miao Y, Jiang Z, Zhou H, et al. PiRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells. Clin Chim Acta. 2011;412:1621–5.
Chu H, Hui G, Yuan L, Shi D, Wang Y, Du M, et al. Identification of novel piRNAs in bladder cancer. Cancer Lett. 2015;356:561–7.
Li Y, Wu X, Gao H, Jin JM, Li AX, Kim YS, et al. Piwi-interacting RNAs (piRNAs) are dysregulated in renal cell carcinoma and associated with tumor metastasis and cancer-specific survival. Mol Med. 2015;21:381–8.
Tan L, Mai D, Zhang B, Jiang X, Zhang J, Bai R, et al. PIWI-interacting RNA-36712 restrains breast cancer progression and chemoresistance by interaction with SEPW1 pseudogene SEPW1P RNA. Mol Cancer. 2019;18. https://doi.org/10.1186/s12943-019-0940-3.
Balaratnam S, West N, Basu S. A piRNA utilizes HILI and HIWI2 mediated pathway to down-regulate ferritin heavy chain 1 mRNA in human somatic cells. Nucleic Acids Res. 2018;46:10635–48.
Lee YJ, Moon SU, Park MG, Jung WY, Park YK, Song SK, et al. Multiplex bioimaging of piRNA molecular pathway-regulated theragnostic effects in a single breast cancer cell using a piRNA molecular beacon. Biomaterials. 2016;101:143–55.
Andersen PR, Tirian L, Vunjak M, Brennecke J. A heterochromatin-dependent transcription machinery drives piRNA expression. Nature. 2017;549:54–9.
Xing Y, Yu T, Wu YN, Roy M, Kim J, Lee C. An expectation-maximization algorithm for probabilistic reconstructions of full-length isoforms from splice graphs. Nucleic Acids Res. 2006;34:3150–60.
Martinez VD, Vucic EA, Thu KL, Hubaux R, Enfield KSS, Pikor LA, et al. Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Sci Rep. 2015;5. https://doi.org/10.1038/srep10423.
Yang Q, Li R, Lyu Q, Hou L, Liu Z, Sun Q, et al. Single-cell CAS-seq reveals a class of short PIWI-interacting RNAs in human oocytes. Nat Commun. 2019;10. https://doi.org/10.1038/s41467-019-11312-8.
Korsunsky I, Parameswaran J, Shapira I, Lovecchio J, Menzin A, Whyte J, et al. Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer. J Investig Med. 2017;65:1068–76.
Pedroza-Torres A, Romero-Córdoba SL, Justo-Garrido M, Salido-Guadarrama I, Rodríguez-Bautista R, Montaño S, et al. MicroRNAs in tumor cell metabolism: roles and therapeutic opportunities. Front Oncol. 2019;9. https://doi.org/10.3389/fonc.2019.01404.
Dudda JC, Salaun B, Ji Y, Palmer DC, Monnot GC, Merck E, et al. MicroRNA-155 is required for effector cd8+ t cell responses to virus infection and cancer. Immunity. 2013;38:742–53.
Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015;518:107–10.
Suzuki HI, Katsura A, Matsuyama H, Miyazono K. MicroRNA regulons in tumor microenvironment. Oncogene 2015;34:3085–94.
Campbell PJ, Getz G, Korbel JO, Stuart JM, Jennings JL, Stein LD, et al. Pan-cancer analysis of whole genomes. Nature. 2020;578:82–93.
Schorn AJ, Gutbrod MJ, LeBlanc C, Martienssen R. LTR-retrotransposon control by tRNA-derived small RNAs. Cell. 2017;170:61–71. e11.
Taft RJ, Glazov EA, Lassmann T, Hayashizaki Y, Carninci P, Mattick JS. Small RNAs derived from snoRNAs. RNA. 2009;15:1233–40.
We regret that the space limitations have prevented us from including all the relevant literature. This work was supported by the Cancer Prevention Research Institute of Texas (CPRIT; RR150085 and RP190570) to the CPRIT Scholar in Cancer Research (LH). This work was also supported by UTHealth Innovation for the Cancer Prevention Research Training Program Postdoctoral Fellowship (Cancer Prevention and Research Institute of Texas grant # RP160015). We thank LeeAnn Chastain for editorial assistance.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhang, Z., Zhang, J., Diao, L. et al. Small non-coding RNAs in human cancer: function, clinical utility, and characterization. Oncogene 40, 1570–1577 (2021). https://doi.org/10.1038/s41388-020-01630-3