Unveiling roles of non-coding RNAs in cancer through advanced technologies

Abstract

Non-coding RNAs (ncRNAs) have emerged as key regulators in tumorigenesis. In this perspective, we briefly review the significance of ncRNA in cancer biology and highlight recent technological advancements in characterization of ncRNA in cancer research. Specifically, we discuss how these advanced approaches, such as Patho-DBiT, CRISPR screens, and snoKARR-seq, hold the potential to revolutionize ncRNA research by offering comprehensive insights into their spatial expression patterns and functional roles.

Keywords

cancer / CRISPR screens / ncRNAs / patho-DBiT / snoKARR-seq / spatial transcriptomics

References

[1] NemethK, Bayraktar R, FerracinM, CalinGA. Non-coding RNAs in disease: from mechanisms to therapeutics. Nat Rev Genet. 2024;25(3):211–32.

[2] ZhangZ, ZhangJ, DiaoL, Han L. Small non-coding RNAs in human cancer: function, clinical utility, and characterization. Oncogene. 2021;40(9):1570–7.

[3] XiangY, YeY, ZhangZ, Han L. Maximizing the utility of cancer transcriptomic data. Trends Cancer. 2018;4(12):823–37.

[4] WinkleM, El-Daly SM, FabbriM, CalinGA. Noncoding RNA therapeutics - challenges and potential solutions. Nat Rev Drug Discov. 2021;20(8):629–51.

[5] LiuCG, LiJ, XuY, LiW, FangSX, Zhang Q, et al. Long noncoding RNAs and circular RNAs in tumor angiogenesis: from mechanisms to clinical significance. Mol Ther Oncolytics. 2021;22:336–54.

[6] LinW, ZhouQ, WangCQ, Zhu L, BiC, ZhangS, et al. LncRNAs regulate metabolism in cancer. Int J Biol Sci. 2020;16(7):1194–206.

[7] PengWX, Koirala P, MoYY. LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 2017;36(41):5661–7.

[8] GuoY, XieY, LuoY. The role of long non-coding RNAs in the tumor immune microenvironment. Front Immunol. 2022;13:851004.

[9] KornienkoAE, GuenzlPM, BarlowDP, Pauler FM. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013;11(1):59.

[10] HuQ, YeY, ChanLC, Li Y, LiangK, LinA, et al. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat Immunol. 2019;20(7):835–51.

[11] RattiM, LampisA, GhidiniM, Salati M, MirchevMB, ValeriN, et al. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as new tools for cancer therapy: first steps from bench to bedside. Target Oncol. 2020;15(3):261–78.

[12] ChenLL, KimVN. Small and long non-coding RNAs: past, present, and future. Cell. 2024;187(23):6451–85.

[13] FernandezN, Cordiner RA, YoungRS, HugN, MaciasS, CáceresJF. Genetic variation and RNA structure regulate microRNA biogenesis. Nat Commun. 2017;8(1):15114.

[14] PekarskyY, Balatti V, CroceCM. BCL2 and miR-15/16: from gene discovery to treatment. Cell Death Differ. 2018;25(1): 21–6.

[15] HeL, Thomson JM, HemannMT, Hernando-MongeE, MuD, GoodsonS, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–33.

[16] AnneseT, TammaR, De GiorgisM, Ribatti D. microRNAs biogenesis, functions and role in tumor angiogenesis. Front Oncol. 2020;10:581007.

[17] MarsonA, LevineSS, ColeMF, Frampton GM, BrambrinkT, JohnstoneS, et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 2008;134(3):521–33.

[18] GrewalSS. Why should cancer biologists care about tRNAs? tRNA synthesis, mRNA translation and the control of growth. Biochim Biophys Acta. 2015;1849(7):898–907.

[19] Gomez-RomanN, Grandori C, EisenmanRN, WhiteRJ. Direct activation of RNA polymerase III transcription by c-Myc. Nature. 2003;421(6920):290–4.

[20] DeverTE, GreenR. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harbor Perspect Biol. 2012;4(7):a013706.

[21] ZhangZ, YeY, GongJ, Ruan H, LiuCJ, XiangY, et al. Global analysis of tRNA and translation factor expression reveals a dynamic landscape of translational regulation in human cancers. Commun Biol. 2018;1:234.

[22] Hernandez-AliasX, Benisty H, SchaeferMH, SerranoL. Translational efficiency across healthy and tumor tissues is proliferation-related. Mol Syst Biol. 2020;16(3):e9275.

[23] ZhangZ, RuanH, LiuCJ, Ye Y, GongJ, DiaoL, et al. tRic: a user-friendly data portal to explore the expression landscape of tRNAs in human cancers. RNA Biol. 2020;17(11):1674–9.

[24] GoodarziH, NguyenHCB, ZhangS, Dill BD, MolinaH, TavazoieSF. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell. 2016;165(6): 1416–27.

[25] WangX, ChowCR, EbineK, Lee J, RosnerMR, PanT, et al. Interaction of tRNA with MEK2 in pancreatic cancer cells. Sci Rep. 2016;6(1):28260.

[26] SantosM, Fidalgo A, VarandaAS, OliveiraC, SantosMAS. tRNA deregulation and its consequences in cancer. Trends Mol Med. 2019;25(10):853–65.

[27] Dupuis-SandovalF, Poirier M, ScottMS. The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdiscip Rev RNA. 2015;6(4):381–97.

[28] LiangJ, WenJ, HuangZ, Chen X, ZhangB, ChuL. Small nucleolar RNAs: insight into their function in cancer. Front Oncol. 2019;9:587.

[29] MannoorK, ShenJ, LiaoJ, Liu Z, JiangF. Small nucleolar RNA signatures of lung tumor-initiating cells. Mol Cancer. 2014;13(1):104.

[30] YangY, ZhangH, XieY, ZhangS, ZhuJ, YinG, et al. Preliminary screening and identification of differentially expressed metastasis-related ncRNAs in ovarian cancer. Oncol Lett. 2018;15:368–74.

[31] CuiL, NakanoK, ObchoeiS, Setoguchi K, MatsumotoM, YamamotoT, 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(1):292–306.e2.

[32] GongJ, LiY, LiuC, XiangY, LiC, YeY, et al. A pan-cancer analysis of the expression and clinical relevance of small nucleolar RNAs in human cancer. Cell Rep. 2017;21(7): 1968–81.

[33] LiuY, RuanH, LiS, YeY, HongW, Gong J, et al. The genetic and pharmacogenomic landscape of snoRNAs in human cancer. Mol Cancer. 2020;19(1):108.

[34] WangR, ChenC, LiuY, LuoM, YangJ, Chen Y, et al. The pharmacogenomic and immune landscape of snoRNAs in human cancers. Cancer Lett. 2024;605:217304.

[35] ChenW, MooreMJ. Spliceosomes. Curr Biol CB. 2015;25(5):R181–3.

[36] DvingeH, Guenthoer J, PorterPL, BradleyRK. RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing. Genome Res. 2019;29(10):1591–604.

[37] InoueD, Guo-Liang C, LiuB, LeeSC, MichelBC, PangalloJ, et al. Spliceosomal disruption of the non-canonical SWI/SNF chromatin remodeling complex in SF3B1 mutant leukemias. Blood. 2019;134(Suppl 1):637.

[38] ShuaiS, SuzukiH, Diaz-NavarroA, NadeuF, KumarSA, Gutierrez-FernandezA, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature. 2019;574(7780):712–6.

[39] SuzukiH, KumarSA, ShuaiS, Diaz-Navarro A, Gutierrez-FernandezA, De AntonellisP, et al. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma. Nature. 2019;574(7780):707–11.

[40] OhJM, Venters CC, DiC, PintoAM, WanL, YounisI, et al. U1 snRNP regulates cancer cell migration and invasion in vitro. Nat Commun. 2020;11:1.

[41] DongX, DingS, YuM, NiuL, XueL, ZhaoY, 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;10:1627.

[42] BradleyRK, Anczuków O. RNA splicing dysregulation and the hallmarks of cancer. Nat Rev Cancer. 2023;23(3): 135–55.

[43] MathiesonW, ThomasGA. Why formalin-fixed, paraffinembedded biospecimens must Be used in genomic medicine: an evidence-based review and conclusion. J Histochem Cytochem. 2020;68(8):543–52.

[44] BaysoyA, BaiZ, SatijaR, Fan R. The technological landscape and applications of single-cell multi-omics. Nat Rev Mol Cell Biol. 2023;24(10):695–713.

[45] BressanD, Battistoni G, HannonGJ. The dawn of spatial omics. Science. 2023;381(6657):eabq4964.

[46] DengY, BaiZ, FanR. Microtechnologies for single-cell and spatial multi-omics. Nat Rev Bioeng. 2023;1(10):769–84.

[47] ChenJ, Larsson L, SwarbrickA, LundebergJ. Spatial landscapes of cancers: insights and opportunities. Nat Rev Clin Oncol. 2024;21(9):660–74.

[48] RaoA, Barkley D, FrançaGS, YanaiI. Exploring tissue architecture using spatial transcriptomics. Nature. 2021;596(7871): 211–20.

[49] JinY, ZuoY, LiG, LiuW, PanY, FanT, et al. Advances in spatial transcriptomics and its applications in cancer research. Mol Cancer. 2024;23(1):129.

[50] ZhangL, ChenD, SongD, Liu X, ZhangY, XuX, et al. Clinical and translational values of spatial transcriptomics. Signal Transduct Targeted Ther. 2022;7(1):111.

[51] BaiZ, ZhangD, GaoY, TaoB, ZhangD, Bao S, et al. Spatially exploring RNA biology in archival formalin-fixed paraffinembedded tissues. Cell. 2024;187(23):6760–79. e24

[52] LiuSJ, Malatesta M, LienBV, SahaP, Thombare SS, HongSJ, et al. CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma. Genome Biol. 2020;21(1):83.

[53] JoungJ, Engreitz JM, KonermannS, AbudayyehOO, Verdine VK, AguetF, et al. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature. 2017;548(7667):343–6.

[54] LiangWW, Müller S, HartSK, WesselsHH, Méndez-Mancilla A, SookdeoA, et al. Transcriptome-scale RNA-targeting CRISPR screens reveal essential lncRNAs in human cells. Cell. 2024: S0092867424012030.

[55] WuT, ChengAY, ZhangY, Xu J, WuJ, WenL, et al. KARR-seq reveals cellular higher-order RNA structures and RNA-RNA interactions. Nat Biotechnol. 2024;42(12):1909–20.

[56] LiuB, WuT, MiaoBA, Ji F, LiuS, WangP, et al. snoRNAfacilitated protein secretion revealed by transcriptome-wide snoRNA target identification. Cell. 2024:S0092867424012698.

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2025 The Author(s). Quantitative Biology published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.