Immune-related long non-coding RNA signature identified prognosis and immunotherapeutic efficiency in bladder cancer (BLCA)

Cancer Cell International - Tập 20 Số 1 - 2020
Rui Cao1, Lushun Yuan2, Bo Ma3, Gang Wang4, Ye Tian1
1Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
2Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
3Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
4Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

Tóm tắt

Abstract Background As bladder cancer was recognized to be immunogenic, dozens of studies have focused on immune biology of BLCA, but little is known about its relationship with the long non-coding RNAs (lncRNAs). Methods LASSO Cox regression model was used to establish immune-related lncRNAs signature (IRLS) in BLCA. The immune infiltration landscape of BLCA was conducted via ssGSEA and immunotherapy response was calculated through TIDE algorithm. Results A total of 82 immune-related lncRNAs were screened out according to spearman correlation analysis with the immune score (|R| > 0.4, p < 0.05). We selected 5 prognostic lncRNAs to construct immune-related lncRNAs signature (IRLS) through LASSO Cox regression analysis. Then we validated that 5 enrolled lncRNAs was downregulated in BLCA tissues and cells when compared with paracancerous tissues and normal bladder epithelium cell. The univariate and multivariate Cox regression analysis both demonstrated the IRLS was a robust independent prognostic factor in overall survival prediction with high accuracy. The GSVA and GSEA also suggested that the IRLS are involved in the immune-related biological processes and pathways which are very well known in the context of BLCA tumorigenesis. In addition, we found that IRLS is strikingly positive correlated with tumour microenvironment (TME) immune cells infiltration and expression of critical immune checkpoints, indicating that the poor prognosis might be caused partly by immunosuppressive TME. Finally, the results from the TIDE analysis revealed that IRLS could efficiently predict the clinical response of immunotherapy in BLCA. Conclusion We have developed a novel IRLS, which have a latent prognostic value for BLCA patients and might facilitate personalized counselling for immunotherapy.

Từ khóa


Tài liệu tham khảo

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017;71(3):447–61.

Soria F, Milla P, Fiorito C, Pisano F, Sogni F, Di Marco M, Pagliarulo V, Dosio F, Gontero P. Efficacy and safety of a new device for intravesical thermochemotherapy in non-grade 3 BCG recurrent NMIBC: a phase I-II study. World J Urol. 2016;34(2):189–95.

Morales A, Eidinger D, Bruce AW. Intracavitary bacillus calmette-guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180–3.

Martinez R, Tapia G, De Muga S, Hernandez A, Cao MG, Teixido C, Urrea V, Garcia E, Pedreno-Lopez S, Ibarz L, et al. Combined assessment of peritumoral Th1/Th2 polarization and peripheral immunity as a new biomarker in the prediction of BCG response in patients with high-risk NMIBC. Oncoimmunology. 2019;8(8):1602460.

Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-Risk non-muscle-invasive bladder cancer-therapy options during intravesical bcg shortage. Curr Urol Rep. 2016;17(9):68.

Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y. Bladder cancer. Nat Rev Dis Primers. 2017;3:17022.

Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer. 2017;123(11):1904–11.

Atkins MB, Clark JI, Quinn DI. Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions. Ann Oncol. 2017;28(7):1484–94.

Inman BA, Longo TA, Ramalingam S, Harrison MR. Atezolizumab: a PD-L1-blocking antibody for bladder cancer. Clin Cancer Res. 2017;23(8):1886–90.

Kapranov P, Cawley SE, Drenkow J, Bekiranov S, Strausberg RL, Fodor SP, Gingeras TR. Large-scale transcriptional activity in chromosomes 21 and 22. Science. 2002;296(5569):916–9.

Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, et al. Landscape of transcription in human cells. Nature. 2012;489(7414):101–8.

Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193(3):651–69.

Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15(1):7–21.

Cabili MN, Dunagin MC, McClanahan PD, Biaesch A, Padovan-Merhar O, Regev A, Rinn JL, Raj A. Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution. Genome Biol. 2015;16:20.

Ma Q, Chang HY. Single-cell profiling of lncRNAs in the developing human brain. Genome Biol. 2016;17:68.

Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504.

Martens-Uzunova ES, Bottcher R, Croce CM, Jenster G, Visakorpi T, Calin GA. Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol. 2014;65(6):1140–51.

Fatima R, Akhade VS, Pal D, Rao SM. Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther. 2015;3:5.

Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

Pan J, Li X, Wu W, Xue M, Hou H, Zhai W, Chen W. Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells. Cancer Lett. 2016;382(1):64–76.

Wang XS, Zhang Z, Wang HC, Cai JL, Xu QW, Li MQ, Chen YC, Qian XP, Lu TJ, Yu LZ, et al. Rapid identification of UCA1 as a very sensitive and specific unique marker for human bladder carcinoma. Clin Cancer Res. 2006;12(16):4851–8.

Tan J, Qiu K, Li M, Liang Y. Double-negative feedback loop between long non-coding RNA TUG1 and miR-145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells. FEBS Lett. 2015;589(20 Pt B):3175–81.

Zhan Y, Du L, Wang L, Jiang X, Zhang S, Li J, Yan K, Duan W, Zhao Y, Wang L, et al. Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer. Mol Cancer. 2018;17(1):142.

Hedegaard J, Lamy P, Nordentoft I, Algaba F, Hoyer S, Ulhoi BP, Vang S, Reinert T, Hermann GG, Mogensen K, et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell. 2016;30(1):27–42.

Cao R, Wang G, Qian K, Chen L, Qian G, Xie C, Dan HC, Jiang W, Wu M, Wu CL, et al. Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPARgamma-SIRT1 feedback loop. J Cancer. 2017;8(12):2282–95.

Cao R, Wang G, Qian K, Chen L, Ju L, Qian G, Wu CL, Dan HC, Jiang W, Wu M, et al. TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARgamma-SIRT1 feedback loop in human bladder cancer cells. Cancer Lett. 2018;414:278–93.

Cao R, Yuan L, Ma B, Wang G, Qiu W, Tian Y. An EMT-related gene signature for the prognosis of human bladder cancer. J Cell Mol Med. 2020;24(1):605–617.

Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108–12.

Wang W, Zhao Z, Yang F, Wang H, Wu F, Liang T, Yan X, Li J, Lan Q, Wang J, et al. An immune-related lncRNA signature for patients with anaplastic gliomas. J Neurooncol. 2018;136(2):263–71.

Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Trevino 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.

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.

Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33(1):1–22.

Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics. 2005;61(1):92–105.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.

Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7.

Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.

Iasonos A, Schrag D, Raj GV, Panageas KS. How to build and interpret a nomogram for cancer prognosis. J Clin Oncol. 2008;26(8):1364–70.

Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782–95.

Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24(10):1550–8.

Wang J, Liu Q, Shyr Y. Dysregulated transcription across diverse cancer types reveals the importance of RNA-binding protein in carcinogenesis. BMC Genomics. 2015;16(Suppl 7):S5.

Cancer Genome Atlas Research N, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45(10):1113–20.

Kanwal R, Gupta K, Gupta S. Cancer epigenetics: an introduction. Methods Mol Biol. 2015;1238:3–25.

Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21(11):1253–61.

Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29(4):452–63.

Chen J, Wang R, Zhang K, Chen LB. Long non-coding RNAs in non-small cell lung cancer as biomarkers and therapeutic targets. J Cell Mol Med. 2014;18(12):2425–36.

Lu Z, Xiao Z, Liu F, Cui M, Li W, Yang Z, Li J, Ye L, Zhang X. Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1). Oncotarget. 2016;7(1):241–54.

Heward JA, Lindsay MA. Long non-coding RNAs in the regulation of the immune response. Trends Immunol. 2014;35(9):408–19.

Carpenter S, Aiello D, Atianand MK, Ricci EP, Gandhi P, Hall LL, Byron M, Monks B, Henry-Bezy M, Lawrence JB, et al. A long noncoding RNA mediates both activation and repression of immune response genes. Science. 2013;341(6147):789–92.

Jiang YZ, Liu YR, Xu XE, Jin X, Hu X, Yu KD, Shao ZM. Transcriptome analysis of triple-negative breast cancer reveals an integrated mRNA-lncRNA signature with predictive and prognostic value. Cancer Res. 2016;76(8):2105–14.

Li J, Chen Z, Tian L, Zhou C, He MY, Gao Y, Wang S, Zhou F, Shi S, Feng X, et al. LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma. Gut. 2014;63(11):1700–10.

Zhou M, Zhao H, Xu W, Bao S, Cheng L, Sun J. Discovery and validation of immune-associated long non-coding RNA biomarkers associated with clinically molecular subtype and prognosis in diffuse large B cell lymphoma. Mol Cancer. 2017;16(1):16.

Khadirnaikar S, Kumar P, Pandi SN, Malik R, Dhanasekaran SM, Shukla SK. Immune associated LncRNAs identify novel prognostic subtypes of renal clear cell carcinoma. Mol Carcinog. 2019;58(4):544–53.

Lee JM, Lee MH, Garon E, Goldman JW, Salehi-Rad R, Baratelli FE, Schaue D, Wang G, Rosen F, Yanagawa J, et al. Phase I trial of intratumoral injection of CCL21 gene-modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8(+) t-cell infiltration. Clin Cancer Res. 2017;23(16):4556–68.

Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22(8):1865–74.

Bauer CA, Kim EY, Marangoni F, Carrizosa E, Claudio NM, Mempel TR. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest. 2014;124(6):2425–40.

Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67(20):10019–26.

Dempke WCM, Fenchel K, Uciechowski P, Dale SP. Second- and third-generation drugs for immuno-oncology treatment-the more the better? Eur J Cancer. 2017;74:55–72.

Le Mercier I, Lines JL, Noelle RJ. Beyond CTLA-4 and PD-1, the generation Z of negative checkpoint regulators. Front Immunol. 2015;6:418.

Thông tin
Thông tin xuất bản

Cancer Cell International

Tập 20 Số 1

Thông tin tác giả