Analysis of Ferroptosis-Related LncRNAs Signatures Associated with Tumor Immune Infiltration and Experimental Validation in Clear Cell Renal Cell Carcinoma

Overview

Journal Int J Gen Med

Publisher Dove Medical Press

Specialty General Medicine

Date 2022 Mar 28

PMID 35342303

Authors

Xinyi Chen

Jingyao Tu

Li Ma

Yongbiao Huang

Chunguang Yang

Xianglin Yuan

Affiliations

Soon will be listed here.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most aggressive subtype of renal cell carcinoma. Ferroptosis is an iron-dependent programmed cell death. Long non-coding RNAs (lncRNAs) emerge as a critical role in regulating cancer progression.

Objective: This study aimed to identify molecular regulation of ferroptosis-related lncRNAs (FRLs) in ccRCC.

Methods: The prognostic value of FRLs was investigated in ccRCC samples downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset. The FRLs were screened out by Pearson correlation test. The 465 FRLs confirmed as potential prognostic factors through univariate Cox regression analysis were entered into Lasso and multivariate Cox regression to build a FRLs prognostic signature. A risk score based on the prognostic model divided ccRCC patients into low- and high-risk groups. A prognostic nomogram, derived from the prognostic signature and integrating clinical characteristics, was constructed. Gene set enrichment analysis (GSEA) revealed the immune- and tumor-associated pathways. Two distinct clusters were identified with different immune signatures through consensus clustering analysis. The prognostic value of some hub FRLs was externally validated via three GEO datasets (GSE46699, GSE53757 and GSE66272) and online databases. Finally, the three FRLs (LINC00460, LINC00941 and LINC02027) were verified through in vitro experiments.

Results: The FRLs prognostic signature, including 7 independent prognostic lncRNAs, exhibited good accuracy in predicting overall survival (OS) of ccRCC patients. This signature was correlated with immune infiltration and immune checkpoint blockade (ICB). We correlated two distinct clusters with immune infiltration signature of ccRCC. The worse prognosis of cluster 2 was probably mediated by immune evasion. We also found that the expression levels of LINC00460 and LINC00941 in ccRCC cell lines were higher than those in HK-2 cells, but LINC02027 showed the inverse trend.

Conclusion: Collectively, our study demonstrated a FRLs prognostic signature which had great clinical value in prognosis assessment.

Citing Articles

Integrated bioinformatics and validation reveal SOX12 as potential biomarker in colon adenocarcinoma based on an immune infiltration-related ceRNA network.

Chen X, Yang M, Tu J, Yuan X J Cancer Res Clin Oncol. 2023; 149(17):15737-15762.

PMID: 37668799 DOI: 10.1007/s00432-023-05316-7.

Identification and in vitro and in vivo validation of the key role of GSDME in pyroptosis-related genes signature in hepatocellular carcinoma.

Chen X, Yang M, Wang L, Wang Y, Tu J, Zhou X BMC Cancer. 2023; 23(1):411.

PMID: 37149620 PMC: 10164321. DOI: 10.1186/s12885-023-10850-1.

A novel oxidative-stress related lncRNA signature predicts the prognosis of clear cell renal cell carcinoma.

Zhang Y, Zhou G, Shi W, Shi W, Hu M, Kong D Sci Rep. 2023; 13(1):5740.

PMID: 37029263 PMC: 10082204. DOI: 10.1038/s41598-023-32891-z.

Regulatory roles of ferroptosis-related non-coding RNAs and their research progress in urological malignancies.

Wang S, Jiang B, Xie D, Li X, Wu G Front Genet. 2023; 14:1133020.

PMID: 36936418 PMC: 10017998. DOI: 10.3389/fgene.2023.1133020.

Identification and validation of a ferroptosis-related lncRNA signature to robustly predict the prognosis, immune microenvironment, and immunotherapy efficiency in patients with clear cell renal cell carcinoma.

Ju L, Shi Y, Liu G PeerJ. 2022; 10:e14506.

PMID: 36570012 PMC: 9774008. DOI: 10.7717/peerj.14506.

References

Liang Y, Wu Y, Chen X, Zhang S, Wang K, Guan X . A novel long noncoding RNA linc00460 up-regulated by CBP/P300 promotes carcinogenesis in esophageal squamous cell carcinoma. Biosci Rep. 2017; 37(5). PMC: 5964888. DOI: 10.1042/BSR20171019. View

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

Wotschofsky Z, Gummlich L, Liep J, Stephan C, Kilic E, Jung K . Integrated microRNA and mRNA Signature Associated with the Transition from the Locally Confined to the Metastasized Clear Cell Renal Cell Carcinoma Exemplified by miR-146-5p. PLoS One. 2016; 11(2):e0148746. PMC: 4747468. DOI: 10.1371/journal.pone.0148746. View

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

Yang W, Ding C, Sun T, Rupprecht G, Lin C, Hsu D . The Hippo Pathway Effector TAZ Regulates Ferroptosis in Renal Cell Carcinoma. Cell Rep. 2019; 28(10):2501-2508.e4. PMC: 10440760. DOI: 10.1016/j.celrep.2019.07.107. View

Li K, Sun D, Gou Q, Ke X, Gong Y, Zuo Y . Long non-coding RNA linc00460 promotes epithelial-mesenchymal transition and cell migration in lung cancer cells. Cancer Lett. 2018; 420:80-90. DOI: 10.1016/j.canlet.2018.01.060. View

Harrow J, Frankish A, Gonzalez J, Tapanari E, Diekhans M, Kokocinski F . GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012; 22(9):1760-74. PMC: 3431492. DOI: 10.1101/gr.135350.111. View

Takeuchi Y, Nishikawa H . Roles of regulatory T cells in cancer immunity. Int Immunol. 2016; 28(8):401-9. PMC: 4986235. DOI: 10.1093/intimm/dxw025. View

Yuan X, Chen L, Li M, Dong P, Xue J, Wang J . Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin Immunol. 2009; 134(3):277-88. DOI: 10.1016/j.clim.2009.10.005. View

10.

Graydon C, Balasko A, Fowke K . Roles, function and relevance of LAG3 in HIV infection. PLoS Pathog. 2019; 15(1):e1007429. PMC: 6336228. DOI: 10.1371/journal.ppat.1007429. View

11.

Seiler M, Huang C, Szalma S, Bhanot G . ConsensusCluster: a software tool for unsupervised cluster discovery in numerical data. OMICS. 2010; 14(1):109-13. DOI: 10.1089/omi.2009.0083. View

12.

Prensner J, Chinnaiyan A . The emergence of lncRNAs in cancer biology. Cancer Discov. 2011; 1(5):391-407. PMC: 3215093. DOI: 10.1158/2159-8290.CD-11-0209. View

13.

Lian Y, Yan C, Xu H, Yang J, Yu Y, Zhou J . A Novel lncRNA, LINC00460, Affects Cell Proliferation and Apoptosis by Regulating KLF2 and CUL4A Expression in Colorectal Cancer. Mol Ther Nucleic Acids. 2018; 12:684-697. PMC: 6083012. DOI: 10.1016/j.omtn.2018.06.012. View

14.

Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T . FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007; 13(3):902-11. DOI: 10.1158/1078-0432.CCR-06-2363. View

15.

Martens-Uzunova E, Bottcher R, Croce C, Jenster G, Visakorpi T, Calin G . Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol. 2013; 65(6):1140-51. DOI: 10.1016/j.eururo.2013.12.003. View

16.

Ye Z, Liu W, Zhuo Q, Hu Q, Liu M, Sun Q . Ferroptosis: Final destination for cancer?. Cell Prolif. 2020; 53(3):e12761. PMC: 7106955. DOI: 10.1111/cpr.12761. View

17.

Finotello F, Mayer C, Plattner C, Laschober G, Rieder D, Hackl H . Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med. 2019; 11(1):34. PMC: 6534875. DOI: 10.1186/s13073-019-0638-6. View

18.

MacLennan S, Imamura M, Lapitan M, Omar M, Lam T, Hilvano-Cabungcal A . Systematic review of perioperative and quality-of-life outcomes following surgical management of localised renal cancer. Eur Urol. 2012; 62(6):1097-117. DOI: 10.1016/j.eururo.2012.07.028. View

19.

Ai Y, Wu S, Zou C, Wei H . LINC00941 promotes oral squamous cell carcinoma progression via activating CAPRIN2 and canonical WNT/β-catenin signaling pathway. J Cell Mol Med. 2020; 24(18):10512-10524. PMC: 7521336. DOI: 10.1111/jcmm.15667. View

20.

Huang C, Workman C, Flies D, Pan X, Marson A, Zhou G . Role of LAG-3 in regulatory T cells. Immunity. 2004; 21(4):503-13. DOI: 10.1016/j.immuni.2004.08.010. View