Abstract
RNA modification serves as a kind of posttranscriptional modification. Besides N6-methyladenosine (m6A), 5-methylcytosine(m5C) is also an important RNA modification. Long non-coding RNAs (lncRNAs) play an important role in tumor progression. Thus, we performed bioinformatic analysis to establish a m5C-related lncRNA signature(m5ClncSig) for hepatocellular carcinoma (HCC). The RNA sequencing data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Pearson correlation coefficient analysis was applied to conduct m5C-related genes and m5C-related lncRNAs co-expressing network. Univariate Cox regression was used to screen the m5C-related lncRNAs with prognosis value. LASSO regression was applied to establish m5ClncSig. Functional analysis including KEGG and GO were performed. The relation between m5ClncSig and immunity was assessed by CIBERSORT and ESTIMATE. RP11-498C9.15 was selected for in vitro validation. A m5ClncSig was established containing 8 lncRNAs with significantly prognosis value. According to risk score calculated by m5ClncSig, high-risk group had worse clinical outcomes than low-risk group. The risk score was validated as an independent prognosis factor. Moreover, the abundances of 11 types of immune cells were significantly different between high-risk group and low-risk group while 8 immune-related genes expressed differently between these two groups. RP11-498C9.15 was validated as a risk factor in HCC progression.
Similar content being viewed by others
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
References
Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for hepatocellular carcinoma: a guide for hepatologists. Hepatology (Baltimore, MD). 2022;75:1604–26.
Thomas DL. Global elimination of chronic hepatitis. N Engl J Med. 2019;380(21):2041–50.
Fan ST. Hepatocellular carcinoma–resection or transplant? Nat Rev Gastroenterol Hepatol. 2012;9(12):732–7.
Liu Z, Lin Y, Zhang J, Zhang Y, Li Y, Liu Z, Li Q, Luo M, Liang R, Ye J. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):447.
Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616.
Tsurusaki M, Murakami T. Surgical and locoregional therapy of HCC: TACE. Liver cancer. 2015;4(3):165–75.
Oerum S, Meynier V, Catala M, Tisné C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021;49(13):7239–55.
Nombela P, Miguel-López B, Blanco S. The role of mA, mC and Ψ RNA modifications in cancer: novel therapeutic opportunities. Mol Cancer. 2021;20(1):18.
Motorin Y, Lyko F, Helm M. 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res. 2010;38(5):1415–30.
Yuan H, Liu J, Zhao L, Wu P, Chen G, Chen Q, Shen P, Yang T, Fan S, Xiao B, et al. Prognostic risk model and tumor immune environment modulation of m5C-related LncRNAs in pancreatic ductal adenocarcinoma. Front Immunol. 2021;12: 800268.
Chen X, Li A, Sun B-F, Yang Y, Han Y-N, Yuan X, Chen R-X, Wei W-S, Liu Y, Gao C-C, et al. 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol. 2019;21(8):978–90.
Yang X, Yang Y, Sun B-F, Chen Y-S, Xu J-W, Lai W-Y, Li A, Wang X, Bhattarai DP, Xiao W, et al. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an mC reader. Cell Res. 2017;27(5):606–25.
Bhan A, Soleimani M, Mandal SS. Long Noncoding RNA and cancer: a new paradigm. Cancer Res. 2017;77(15):3965–81.
Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22(9):1775–89.
Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154(1):26–46.
Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172(3):393–407.
Huang Z, Zhou J-K, Peng Y, He W, Huang C. The role of long noncoding RNAs in hepatocellular carcinoma. Mol Cancer. 2020;19(1):77.
Klingenberg M, Groß M, Goyal A, Polycarpou-Schwarz M, Miersch T, Ernst A-S, Leupold J, Patil N, Warnken U, Allgayer H, et al. The long noncoding RNA cancer susceptibility 9 and RNA binding protein heterogeneous nuclear ribonucleoprotein L form a complex and coregulate genes linked to AKT signaling. Hepatology (Baltimore, MD). 2018;68(5):1817–32.
Wang Y, Yang L, Chen T, Liu X, Guo Y, Zhu Q, Tong X, Yang W, Xu Q, Huang D, et al. A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194-5p/FOXA1 axis. Mol Cancer. 2019;18(1):28.
Wang K, Zhong W, Long Z, Guo Y, Zhong C, Yang T, Wang S, Lai H, Lu J, Zheng P, et al. 5-Methylcytosine RNA methyltransferases-related long non-coding RNA to develop and validate biochemical recurrence signature in prostate cancer. Front Mol Biosci. 2021;8: 775304.
Pan J, Huang Z, Xu Y. m5C-related lncRNAs predict overall survival of patients and regulate the tumor immune microenvironment in lung adenocarcinoma. Front Cell Dev Biol. 2021;9: 671821.
Shen H, Ontiveros RJ, Owens MC, Liu MY, Ghanty U, Kohli RM, Liu KF. TET-mediated 5-methylcytosine oxidation in tRNA promotes translation. J Biol Chem. 2021;296: 100087.
Zou F, Tu R, Duan B, Yang Z, Ping Z, Song X, Chen S, Price A, Li H, Scott A, et al. YBX1 homolog YPS promotes ovarian germ line stem cell development by preferentially recognizing 5-methylcytosine RNAs. Proc Natl Acad Sci U S A. 2020;117(7):3603–9.
Chen H, Yang H, Zhu X, Yadav T, Ouyang J, Truesdell SS, Tan J, Wang Y, Duan M, Wei L, et al. mC modification of mRNA serves a DNA damage code to promote homologous recombination. Nat Commun. 2020;11(1):2834.
Plitta B, Adamska E, Giel-Pietraszuk M, Fedoruk-Wyszomirska A, Naskręt-Barciszewska M, Markiewicz WT, Barciszewski J. New cytosine derivatives as inhibitors of DNA methylation. Eur J Med Chem. 2012;55:243–54.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.
Guo G, Wang H, Shi X, Ye L, Yan K, Chen Z, Zhang H, Jin Z, Xue X. Disease activity-associated alteration of mRNA m C methylation in CD4 T cells of systemic lupus erythematosus. Front Cell Dev Biol. 2020;8:430.
Luo Y, Feng J, Xu Q, Wang W, Wang X. NSun2 deficiency protects endothelium from inflammation via mRNA methylation of ICAM-1. Circ Res. 2016;118(6):944–56.
Guo G, Pan K, Fang S, Ye L, Tong X, Wang Z, Xue X, Zhang H. Advances in mRNA 5-methylcytosine modifications: Detection, effectors, biological functions, and clinical relevance. Mol Ther Nucleic Acids. 2021;26:575–93.
Mei L, Shen C, Miao R, Wang J-Z, Cao M-D, Zhang Y-S, Shi L-H, Zhao G-H, Wang M-H, Wu L-S, et al. RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57 by an mC-dependent manner. Cell Death Dis. 2020;11(4):270.
He Y, Yu X, Li J, Zhang Q, Zheng Q, Guo W. Role of mC-related regulatory genes in the diagnosis and prognosis of hepatocellular carcinoma. Am J Transl Res. 2020;12(3):912–22.
Hu Y, Chen C, Tong X, Chen S, Hu X, Pan B, Sun X, Chen Z, Shi X, Hu Y, et al. NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. Cell Death Dis. 2021;12(9):842.
Liu Y, Zheng S, Wang T, Fang Z, Kong J, Liu J. Identification of the expression patterns and potential prognostic role of 5-methylcytosine regulators in hepatocellular carcinoma. Front Cell Dev Biol. 2022;10: 842220.
Huang Y, Huang C, Jiang X, Yan Y, Zhuang K, Liu F, Li P, Wen Y. Exploration of potential roles of m5C-related regulators in colon adenocarcinoma prognosis. Front Genet. 2022;13: 816173.
Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, Li J, An P, Lu L, Luo N, et al. mA-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019;18(1):87.
Sun Z, Xue S, Zhang M, Xu H, Hu X, Chen S, Liu Y, Guo M, Cui H. Aberrant NSUN2-mediated mC modification of H19 lncRNA is associated with poor differentiation of hepatocellular carcinoma. Oncogene. 2020;39(45):6906–19.
Vinuesa CG, Linterman MA, Yu D, MacLennan ICM. Follicular helper T cells. Annu Rev Immunol. 2016;34:335–68.
Zhou Z-Q, Tong D-N, Guan J, Tan H-W, Zhao L-D, Zhu Y, Yao J, Yang J, Zhang Z-Y. Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages. Am J Transl Res. 2016;8(7):2926–36.
Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27(1):109–18.
Funding
This study was supported by the National Natural Science Foundation of China (grant number 81670595 and 81970568).
Author information
Authors and Affiliations
Contributions
JL and JX: designed this work. JL and HW: performed the bioinformatics analysis. DC: performed the wet experiments. WC and ZH: wrote the manuscript. All authors have read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethics approval and consent to participate
The studies involving human participants were reviewed and approved by Medical Ethics Committee of Shanghai General Hospital (approved number: 2022SQ154). The patients provided their written informed consent to participate in this study.
Consent for publication
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
13577_2022_845_MOESM2_ESM.docx
Supplementary file2 Table S2 368 HCC samples were divided into high-risk group and low-risk group according to the risk score. (DOCX 20 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lu, J., Wang, H., Cao, W. et al. Construction of a m5C-related long non-coding RNA signature for the prognosis of hepatocellular carcinoma. Human Cell 36, 712–724 (2023). https://doi.org/10.1007/s13577-022-00845-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13577-022-00845-8