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Cancer Cell International
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Kidney Cancer | Primary research

Construction and validation of a ferroptosis-related long noncoding RNA signature in clear cell renal cell carcinoma

Authors: Zhenpeng Zhu, Cuijian Zhang, Jinqin Qian, Ninghan Feng, Weijie Zhu, Yang Wang, Yanqing Gong, Xuesong Li, Jian Lin, Liqun Zhou

Published in: Cancer Cell International | Issue 1/2022

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Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of lipid-reactive oxygen species. Ferroptosis, due to the lipid peroxidation, has been reported to be strongly correlated with tumorigenesis and progression. However, the functions of the ferroptosis process in ccRCC remain unclear.

Methods

After sample cleaning, data integration, and batch effect removal, we used the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases to screen out the expression and prognostic value of ferroptosis-related lncRNAs and then performed the molecular subtyping using the K-means method. Then, the functional pathway enrichment and immune microenvironment infiltration between the different clusters were carried out. The results showed a significant difference in immune cell infiltration between the two clusters and the associated marker responded to individualized differences in treatment. Then, least absolute shrinkage and selection operator (LASSO) Cox regression was used to establish a prognostic signature based on 5 lncRNAs. This signature could accurately predicted patient prognosis and served as an independent clinical risk factor. We then combined significant clinical parameters in multivariate Cox regression and the prognostic signature to construct a clinical predictive nomogram, which provides appropriate guidance for predicting the overall survival of ccRCC patients.

Results

The prognostic differentially expressed ferroptosis-related LncRNAs (DEFRlncRNAs) were found, and 5 lncRNAs were finally used to establish the prognostic signature in the TCGA cohort, with subsequently validation in the internal and external cohorts. Moreover, we conducted the molecular subtyping and divided the patients in the TCGA cohort into two clusters showing differences in Hallmark pathways, immune infiltration, immune target expression, and drug therapies. Differences between clusters contributed to individualizing treatment. Furthermore, a nomogram was established to better predict the clinical outcomes of the ccRCC patients.

Conclusions

Our study conducted molecular subtyping and established a novel predictive signature based on the ferroptosis-related lncRNAs, which contributed to the prognostic prediction and individualizing treatment of ccRCC patients.
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Literature
1.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.CrossRefPubMed
2.
Jonasch E, Walker CL, Rathmell WK. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17(4):245–61.PubMedCrossRef
3.
Warren AY, Harrison D. WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies. World J Urol. 2018;36(12):1913–26.PubMedPubMedCentralCrossRef
4.
5.
Sanfrancesco JM, Cheng L. Complexity of the genomic landscape of renal cell carcinoma: Implications for targeted therapy and precision immuno-oncology. Crit Rev Oncol Hematol. 2017;119:23–8.PubMedCrossRef
6.
7.
Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Free Radic Biol Med. 2019;133:130–43.PubMedCrossRef
8.
Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12(1):34.PubMedPubMedCentralCrossRef
9.
Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108.PubMedCrossRef
10.
Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019;31(51):e1904197.PubMedCrossRef
11.
Ransohoff JD, Wei Y, Khavari PA. The functions and unique features of long intergenic non-coding RNA. Nat Rev Mol Cell Biol. 2018;19(3):143–57.PubMedCrossRef
12.
Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, et al. A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res. 2018;78(13):3484–96.PubMedPubMedCentralCrossRef
13.
Wang M, Mao C, Ouyang L, Liu Y, Lai W, Liu N, et al. Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ. 2019;26(11):2329–43.PubMedPubMedCentralCrossRef
14.
Wang Z, Chen X, Liu N, Shi Y, Liu Y, Ouyang L, et al. A nuclear long non-coding RNA LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. Mol Ther. 2021;29(1):263–74.PubMedCrossRef
15.
Zhu L, Yang F, Wang L, Dong L, Huang Z, Wang G, et al. Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma. Cancer Cell Int. 2021;21(1):124.PubMedPubMedCentralCrossRef
16.
Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–49.PubMedCrossRef
17.
Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.PubMedCrossRef
18.
Greenberg SA, Sanoudou D, Haslett JN, Kohane IS, Kunkel LM, Beggs AH, et al. Molecular profiles of inflammatory myopathies. Neurology. 2002;59(8):1170–82.PubMedCrossRef
19.
Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26(12):1572–3.PubMedPubMedCentralCrossRef
20.
21.
22.
Geeleher P, Cox NJ, Huang RS. Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol. 2014;15(3):R47.PubMedPubMedCentralCrossRef
23.
Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18(1):248–62.PubMedCrossRef
24.
Hackl H, Charoentong P, Finotello F, Trajanoski Z. Computational genomics tools for dissecting tumour-immune cell interactions. Nat Rev Genet. 2016;17(8):441–58.PubMedCrossRef
25.
Hong W, Liang L, Gu Y, Qi Z, Qiu H, Yang X, et al. Immune-related lncRNA to construct novel signature and predict the immune landscape of human hepatocellular carcinoma. Mol Ther Nucleic Acids. 2020;22:937–47.PubMedPubMedCentralCrossRef
26.
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.PubMedCrossRef
27.
28.
Nguyen CT, Campbell SC. Staging of renal cell carcinoma: past, present, and future. Clin Genitourin Cancer. 2006;5(3):190–7.PubMedCrossRef
29.
Elkassem AA, Allen BC, Sharbidre KG, Rais-Bahrami S, Smith AD. Update on the role of imaging in clinical staging and restaging of renal cell carcinoma based on the AJCC 8th edition from the AJR special series on cancer staging. AJR Am J Roentgenol. 2021;217(3):541–55.PubMedCrossRef
30.
Yu H, Guo P, Xie X, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21(4):648–57.PubMedCrossRef
31.
Mou Y, Wu J, Zhang Y, Abdihamid O, Duan C, Li B. Low expression of ferritinophagy-related NCOA4 gene in relation to unfavorable outcome and defective immune cells infiltration in clear cell renal carcinoma. BMC Cancer. 2021;21(1):18.PubMedPubMedCentralCrossRef
32.
Wang J, Yin X, He W, Xue W, Zhang J, Huang Y. SUV39H1 deficiency suppresses clear cell renal cell carcinoma growth by inducing ferroptosis. Acta Pharm Sin B. 2021;11(2):406–19.PubMedCrossRef
33.
Lu J, Xu F, Lu H. LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci. 2020;260:118305.PubMedCrossRef
34.
35.
Zhong W, Zhang F, Huang C, Lin Y, Huang J. Identification of epithelial-mesenchymal transition-related lncRNA with prognosis and molecular subtypes in clear cell renal cell carcinoma. Front Oncol. 2020;10:591254.PubMedPubMedCentralCrossRef
36.
Xiong Y, Wang Z, Zhou Q, Zeng H, Zhang H, Liu Z, et al. Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients. J Immunother Cancer. 2020;8(1):e000447.PubMedPubMedCentralCrossRef
37.
Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61(13):5132–6.PubMed
38.
Giraldo NA, Becht E, Pagès F, Skliris G, Verkarre V, Vano Y, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. 2015;21(13):3031–40.PubMedCrossRef
39.
Yang H, Xiong X, Li H. Development and interpretation of a genomic instability derived lncRNAs based risk signature as a predictor of prognosis for clear cell renal cell carcinoma patients. Front Oncol. 2021;11:678253.PubMedPubMedCentralCrossRef
40.
Wang Y, Yan K, Wang L, Bi J. Genome instability-related long non-coding RNA in clear renal cell carcinoma determined using computational biology. BMC Cancer. 2021;21(1):727.PubMedPubMedCentralCrossRef
41.
Zhang S, Zhang F, Niu Y, Yu S. Aberration of lncRNA LINC00460 is a promising prognosis factor and associated with progression of clear cell renal cell carcinoma. Cancer Manag Res. 2021;13:6489–97.PubMedPubMedCentralCrossRef
42.
Meng D-F, Shao H, Feng C-B. LINC00894 enhances the progression of breast cancer by sponging miR-429 to regulate ZEB1 expression. Onco Targets Ther. 2021;14:3395–407.PubMedPubMedCentralCrossRef
43.
Zhu H, Shan Y, Ge K, Lu J, Kong W, Jia C. LncRNA CYTOR promotes pancreatic cancer cell proliferation and migration by sponging miR-205-5p. Pancreatology. 2020;20(6):1139–48.PubMedCrossRef
44.
Hu B, Yang X-B, Yang X, Sang X-T. LncRNA CYTOR affects the proliferation, cell cycle and apoptosis of hepatocellular carcinoma cells by regulating the miR-125b-5p/KIAA1522 axis. Aging (Albany NY). 2020;13(2):2626–39.CrossRef
45.
Liu H, Zhang X, Jin X, Yang Y, Liang G, Ma Y, et al. Long noncoding RNA VPS9D1-AS1 sequesters microRNA-525-5p to promote the oncogenicity of colorectal cancer cells by upregulating HMGA1. Cancer Manag Res. 2020;12:9915–28.PubMedPubMedCentralCrossRef
46.
Liang X, Chen Z, Wu G. FOXD2-AS1 predicts dismal prognosis for oral squamous cell carcinoma and regulates cell proliferation. Cell Transplant. 2020;29:963689720964411.PubMed
47.
Xue W, Shen Z, Li L, Zheng Y, Yan D, Kan Q, et al. Long non-coding RNAs MACC1-AS1 and FOXD2-AS1 mediate NSD2-induced cisplatin resistance in esophageal squamous cell carcinoma. Mol Ther Nucleic Acids. 2021;23:592–602.PubMedCrossRef
Metadata
Title
Construction and validation of a ferroptosis-related long noncoding RNA signature in clear cell renal cell carcinoma
Authors
Zhenpeng Zhu
Cuijian Zhang
Jinqin Qian
Ninghan Feng
Weijie Zhu
Yang Wang
Yanqing Gong
Xuesong Li
Jian Lin
Liqun Zhou
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02700-0

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