Abstract
Purpose
Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer.
Methods
Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study.
Results
Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study.
Conclusions
The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.
Similar content being viewed by others
Data availability
All public data analysed in this study were from database of TCGA (https://portal.gdc.cancer.gov/). All procedure in this study followed corresponding guidelines and relative policies of above public database.
Abbreviations
- TCGA:
-
The cancer genome atlas
- m6A:
-
N6-methyladenosine
- lncRNA:
-
Long non-coding RNAs
- PD-1:
-
Immune checkpoint programmed cell death 1
- PD-L1:
-
Immune checkpoint programmed cell death 1 ligand
- DEGs:
-
Differentially expressed genes
- CTLA-4:
-
Cytotoxic T lymphocyte antigen 4
- LASSO:
-
Least absolute shrinkage and selection operator analysis
- ROC:
-
Receiver operating characteristic
- GSVA:
-
Gene set variation analysis
- eBCR:
-
Early biochemical recurrence
- PSA:
-
Prostate-specific antigen
- IC50:
-
The half maximal inhibitory concentration
References
Bi Z, Liu Y, Zhao Y, Yao Y, Wu R, Liu Q et al (2019) A dynamic reversible RNA N(6) -methyladenosine modification: current status and perspectives. J Cell Physiol 234(6):7948–7956
Bilusic M, Madan RA, Gulley JL (2017) Immunotherapy of prostate cancer: facts and hopes. Clin Cancer Res 23(22):6764–6770
Boettcher AN, Usman A, Morgans A, VanderWeele DJ, Sosman J, Wu JD (2019) Past, current, and future of immunotherapies for prostate cancer. Front Oncol 9:884
Byron SA, Van Keuren-Jensen KR, Engelthaler DM, Carpten JD, Craig DW (2016) Translating RNA sequencing into clinical diagnostics: opportunities and challenges. Nat Rev Genet 17(5):257–271
Cha HR, Lee JH, Ponnazhagan S (2020) Revisiting immunotherapy: a focus on prostate cancer. Can Res 80(8):1615–1623
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F et al (2016) Cancer statistics in China, 2015. CA 66(2):115–32
Chen YA, Cheng L, Zhang Y, Peng L, Yang HG (2020) LncRNA RUSC1-AS1 promotes the proliferation of hepatocellular carcinoma cells through modulating NOTCH signaling. Neoplasma 67(6):1204–1213
Dall’Era MA, Albertsen PC, Bangma C, Carroll PR, Carter HB, Cooperberg MR et al (2012) Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 62(6):976–983
D’Amico AV, Whittington R, Malkowicz SB, Wu YH, Chen M, Art M et al (2000) Combination of the preoperative PSA level, biopsy gleason score, percentage of positive biopsies, and MRI T-stage to predict early PSA failure in men with clinically localized prostate cancer. Urology 55(4):572–577
De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D et al (2014) Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE–5-a population-based study. Lancet Oncol 15(1):23–34
Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C et al (2013) Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS ONE 8(6):e66855
Graff JN, Alumkal JJ, Thompson RF, Moran A, Beer T (2018) Pembrolizumab (Pembro) plus enzalutamide (Enz) in metastatic castration resistant prostate cancer (mCRPC): extended follow up. J Clin Oncol 36:5047
Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F et al (2012) GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 22(9):1760–1774
Howard N, Clementino M, Kim D, Wang L, Verma A, Shi X et al (2019) New developments in mechanisms of prostate cancer progression. Semin Cancer Biol 57:111–116
Hu CC, Liang YW, Hu JL, Liu LF, Liang JW, Wang R (2019) LncRNA RUSC1-AS1 promotes the proliferation of breast cancer cells by epigenetic silence of KLF2 and CDKN1A. Eur Rev Med Pharmacol Sci 23(15):6602–6611
Hu D, Jiang L, Luo S, Zhao X, Hu H, Zhao G et al (2020) Development of an autophagy-related gene expression signature for prognosis prediction in prostate cancer patients. J Transl Med 18(1):160
Hua JT, Ahmed M, Guo H, Zhang Y, Chen S, Soares F et al (2018) Risk SNP-mediated promoter-enhancer switching drives prostate cancer through lncRNA PCAT19. Cell 174(3):564–75.e18
Intasqui P, Bertolla RP, Sadi MV (2018) Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives. Expert Rev Proteom 15(1):65–79
Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y et al (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47(3):199–208
Johansson JE, Adami HO, Andersson SO, Bergström R, Holmberg L, Krusemo UB (1992) High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 267(16):2191–2196
Jung KW, Park S, Kong HJ, Won YJ, Lee JY, Seo HG et al (2012) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. Cancer Res Treat 44(1):11–24
Kessler B, Albertsen P (2003) The natural history of prostate cancer. Urol Clinics N Am 30(2):219–226
Kim PJ, Park JY, Kim HG, Cho YM, Go H (2017) Dishevelled segment polarity protein 3 (DVL3): a novel and easily applicable recurrence predictor in localised prostate adenocarcinoma. BJU Int 120(3):343–350
Laccetti AL, Subudhi SK (2017) Immunotherapy for metastatic prostate cancer: immuno-cold or the tip of the iceberg? Curr Opin Urol 27(6):566–571
Lalonde E, Ishkanian AS, Sykes J, Fraser M, Ross-Adams H, Erho N et al (2014) Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 15(13):1521–1532
Li X, Dang Y (2021) Inhibition of GARS1-DT protects against hypoxic injury in H9C2 cardiomyocytes via sponging miR-212-5p. J Cardiovasc Pharmacol 78(5):e714–e721
Li S, Fong KW, Gritsina G, Zhang A, Zhao JC, Kim J et al (2019) Activation of MAPK signaling by CXCR7 leads to enzalutamide resistance in prostate cancer. Can Res 79(10):2580–2592
Li Z, Li F, Peng Y, Fang J, Zhou J (2020) Identification of three m6A-related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma. Cancer Med 9(5):1877–1889
Liu B, Li X, Li J, Jin H, Jia H, Ge X (2020) Construction and validation of a robust cancer stem cell-associated gene set-based signature to predict early biochemical recurrence in prostate cancer. Dis Markers 2020:8860788
Liu H, Wan J, Feng Q, Li J, Liu J, Cui S (2022) Long non-coding RNA SOS1-IT1 promotes endometrial cancer progression by regulating hypoxia signaling pathway. J Cell Commun Signal 16(2):253–270
Lu X, Jiang L, Zhang L, Zhu Y, Hu W, Wang J et al (2019) Immune signature-based subtypes of cervical squamous cell carcinoma tightly associated with human papillomavirus type 16 expression, molecular features, and clinical outcome. Neoplasia (New York, NY) 21(6):591–601
Luo HW, Chen QB, Wan YP, Chen GX, Zhuo YJ, Cai ZD et al (2016) Protein regulator of cytokinesis 1 overexpression predicts biochemical recurrence in men with prostate cancer. Biomed Pharmacother 78:116–20
May EJ, Viers LD, Viers BR, Kawashima A, Kwon ED, Karnes RJ et al (2016) Prostate cancer post-treatment follow-up and recurrence evaluation. Abdominal Radiol (New York) 41(5):862–876
Milosevic M, Warde P, Ménard C, Chung P, Toi A, Ishkanian A et al (2012) Tumor hypoxia predicts biochemical failure following radiotherapy for clinically localized prostate cancer. Clin Cancer Res 18(7):2108–2114
Mohler JL, Antonarakis ES, Armstrong AJ, D’Amico AV, Davis BJ, Dorff T et al (2019) Prostate cancer, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Comprehensive Cancer Netw 17(5):479–505
Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M et al (2017) EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 71(4):618–29
Muniyan S, Chen SJ, Lin FF, Wang Z, Mehta PP, Batra SK et al (2015) ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells. Cell Signal 27(11):2261–2271
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457
Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L et al (2019) RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer 18(1):46
Ong CW, Maxwell P, Alvi MA, McQuaid S, Waugh D, Mills I et al (2018) A gene signature associated with PTEN activation defines good prognosis intermediate risk prostate cancer cases. J Pathol Clin Res 4(2):103–113
Roobol MJ, Carlsson SV (2013) Risk stratification in prostate cancer screening. Nat Rev Urol 10(1):38–48
Sanchez Calle A, Kawamura Y, Yamamoto Y, Takeshita F, Ochiya T (2018) Emerging roles of long non-coding RNA in cancer. Cancer Sci 109(7):2093–2100
Sandblom G, Ladjevardi S, Garmo H, Varenhorst E (2008) The impact of prostate-specific antigen level at diagnosis on the relative survival of 28,531 men with localized carcinoma of the prostate. Cancer 112(4):813–819
Shang Z, Yu J, Sun L, Tian J, Zhu S, Zhang B et al (2019) LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex. Nucleic Acids Res 47(8):4211–4225
Shao N, Wang Y, Jiang WY, Qiao D, Zhang SG, Wu Y et al (2013) Immunotherapy and endothelin receptor antagonists for treatment of castration-resistant prostate cancer. Int J Cancer 133(7):1743–1750
Shao N, Tang H, Qu Y, Wan F, Ye D (2019) Development and validation of lncRNAs-based nomogram for prediction of biochemical recurrence in prostate cancer by bioinformatics analysis. J Cancer 10(13):2927–2934
Shao N, Tang H, Mi Y, Zhu Y, Wan F, Ye D (2020) A novel gene signature to predict immune infiltration and outcome in patients with prostate cancer. Oncoimmunology 9(1):1762473
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA 67(1):7–30
Sinnott JA, Peisch SF, Tyekucheva S, Gerke T, Lis R, Rider JR et al (2017) Prognostic utility of a new mRNA expression signature of Gleason score. Clin Cancer Res 23(1):81–87
Song B, Park SH, Zhao JC, Fong KW, Li S, Lee Y et al (2019) Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression. J Clin Investig 129(2):569–582
Sun M, Geng D, Li S, Chen Z, Zhao W (2018) LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells. Biol Chem 399(4):387–395
Tollefson MK, Blute ML, Rangel LJ, Bergstralh EJ, Boorjian SA, Karnes RJ (2010) The effect of Gleason score on the predictive value of prostate-specific antigen doubling time. BJU Int 105(10):1381–1385
Tsivian M, Sun L, Mouraviev V, Madden JF, Mayes JM, Moul JW et al (2009) Changes in Gleason score grading and their effect in predicting outcome after radical prostatectomy. Urology 74(5):1090–1093
Vitkin N, Nersesian S, Siemens DR, Koti M (2019) The tumor immune contexture of prostate cancer. Front Immunol 10:603
Wiegel T, Bottke D, Steiner U, Siegmann A, Golz R, Störkel S et al (2009) Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96–02/AUO AP 09/95. J Clin Oncol 27(18):2924–2930
Wiegel T, Bartkowiak D, Bottke D, Bronner C, Steiner U, Siegmann A et al (2014) Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96–02/AUO AP 09/95 trial. Eur Urol 66(2):243–250
Wu M, Huang Y, Chen T, Wang W, Yang S, Ye Z et al (2019) LncRNA MEG3 inhibits the progression of prostate cancer by modulating miR-9-5p/QKI-5 axis. J Cell Mol Med 23(1):29–38
Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S et al (2013) Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 41:955–61
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W et al (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612
You Z, Liu C, Wang C, Ling Z, Wang Y, Wang Y et al (2019) LncRNA CCAT1 promotes prostate cancer cell proliferation by interacting with DDX5 and MIR-28-5P. Mol Cancer Ther 18(12):2469–2479
Funding
This work was not supported by external funders.
Author information
Authors and Affiliations
Contributions
JCL and JYW provied the conceptualization. WZ and JWW performed the methodology and formal analysis. HRX and ZTL prepared figures 1-7. JCL and ZPZ writed the original draft. YGZ edited the tables. All authors reviewed the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
All authors have no conflicts of interest to declare.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
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.
432_2022_4040_MOESM11_ESM.jpg
Supplementary file11 Relationships between expressions of 25 prognostic lncRNAs and immune checkpoints. A–C Prognostic lncRNAs significantly correlated with PD1, PD-L1 and CTLA-4 in prostate cancers (JPG 2381 KB)
432_2022_4040_MOESM12_ESM.jpg
Supplementary file12 GSEA analysis. A–F Significantly enriched activities in GSEA analysis for cluster 2. (p < 0.01) G–L Significantly enriched activities in GSEA analysis for cluster 1. (p < 0.05) (JPG 2451 KB)
432_2022_4040_MOESM13_ESM.jpg
Supplementary file13 The lncRNA risk signature poses excellent predictive performance for eBCR-free survivals in various subgroups. A–B High risk group tended to obtain significantly poorer eBCR-free survivals in patients with both PSA ≥ 4 ng/ml and PSA < 4ng/ml. C–D High risk group tended to obtain significantly poorer eBCR-free survivals in patients with both Gleason score 6-7 and Gleason score 8–10 (JPG 871 KB)
432_2022_4040_MOESM14_ESM.jpg
Supplementary file14 Risk score significantly correlated with infiltrations of various immune cells. A–C The risk score positively correlated with infiltrations of activated memory CD4 T cells, resting memory CD4 T cells and M1 Macrophages. D–E Risk score negatively correlated with infiltrations of resting mast cells and Neutrophils (JPG 630 KB)
Rights and permissions
About this article
Cite this article
Liu, J., Zhang, W., Wang, J. et al. Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer. J Cancer Res Clin Oncol 149, 1969–1983 (2023). https://doi.org/10.1007/s00432-022-04040-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-022-04040-y