Integrated Analysis of Single-cell and Bulk-RNA Sequencing for the Cellular Senescence in Prognosis of Lung Adenocarcinoma

Overview

Journal Sci Rep

Date 2025 Jan 9

PMID 39789322

Authors

Fengqiang Yu

Liangyu Zhang

Xun Zhang

Jianshen Zeng

Fancai Lai

Affiliations

Soon will be listed here.

Abstract

Non-small cell lung cancer (NSCLC), half of which are lung adenocarcinoma (LUAD), is one of the most widely spread cancers in the world. Telomerase, which maintains telomere length and chromosomal integrity, enables cancer cells to avoid replicative senescence. When telomerase is inhibited, cancer cells' senescence began, preventing them from growing indefinitely. Cellular senescence and telomeres are intrinsically linked. As of yet, still laking a systematic study of the involvement of telomere-senescence related genes in lung adenocarcinoma development. In this study, myeloid cells were identified as the cell type which are most correlated with cellular senescence based on its highest telomere-related gene activity. GO, KEGG, GSEA and GSVA analyses were used to explore the biological function of telomere-senescence related genes in LUAD. The combined analysis of single-cell RNA-sequencing and bulk-RNA sequencing identified a gene signature composed of 14 genes which can accurately predict the prognosis of patients with LUAD. In one training and four validation sets, patients with higher Telomere Related Gene Signature (TRGS) had a worse prognosis than those with lower TRGS. Different TRGS patient groups showed varying degrees of immune cell infiltration, frequency of gene missense mutation, sensitivity to different drugs, and tumor mutation burden (TMB). Collectively, we developed a brand new signature composed of telomere-senescence related genes that can accurately predicts patients' prognosis in LUAD, which provides new insights for future research into the role of cellular senescence in LUAD.

References

Abdallah P, Luciano P, Runge K, Lisby M, Geli V, Gilson E . A two-step model for senescence triggered by a single critically short telomere. Nat Cell Biol. 2009; 11(8):988-93. PMC: 4025917. DOI: 10.1038/ncb1911. View

Lu T, Yang X, Huang Y, Zhao M, Li M, Ma K . Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades. Cancer Manag Res. 2019; 11:943-953. PMC: 6345192. DOI: 10.2147/CMAR.S187317. View

Vertecchi E, Rizzo A, Salvati E . Telomere Targeting Approaches in Cancer: Beyond Length Maintenance. Int J Mol Sci. 2022; 23(7). PMC: 8998427. DOI: 10.3390/ijms23073784. View

Li J, Wang Y, Li Q, Xue J, Wang Z, Yuan X . Downregulation of FBP1 Promotes Tumor Metastasis and Indicates Poor Prognosis in Gastric Cancer via Regulating Epithelial-Mesenchymal Transition. PLoS One. 2016; 11(12):e0167857. PMC: 5158319. DOI: 10.1371/journal.pone.0167857. View

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

Maeda H, Yao H, Go H, Huntington K, De Paepe M, Dennery P . Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung epithelial cells. Respir Res. 2022; 23(1):340. PMC: 9741793. DOI: 10.1186/s12931-022-02263-8. View

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Giaj Levra M . Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27(suppl 5):v1-v27. DOI: 10.1093/annonc/mdw326. View

Li X, Wang T, Li M, Bao X, Ma T, Yang C . Comprehensive analysis of BUBs gene family in lung adenocarcinoma with immunological analysis. Aging (Albany NY). 2023; 15(3):810-829. PMC: 9970319. DOI: 10.18632/aging.204517. View

10.

Ru B, Wong C, Tong Y, Zhong J, Zhong S, Wu W . TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics. 2019; 35(20):4200-4202. DOI: 10.1093/bioinformatics/btz210. View

11.

Chan S, Blackburn E . Telomeres and telomerase. Philos Trans R Soc Lond B Biol Sci. 2004; 359(1441):109-21. PMC: 1693310. DOI: 10.1098/rstb.2003.1370. View

12.

Yang W, Soares J, Greninger P, Edelman E, Lightfoot H, Forbes S . Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2012; 41(Database issue):D955-61. PMC: 3531057. DOI: 10.1093/nar/gks1111. View

13.

Kuilman T, Michaloglou C, Mooi W, Peeper D . The essence of senescence. Genes Dev. 2010; 24(22):2463-79. PMC: 2975923. DOI: 10.1101/gad.1971610. View

14.

Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A . Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev. 2019; 99(2):1047-1078. DOI: 10.1152/physrev.00020.2018. View

15.

Gorgoulis V, Adams P, Alimonti A, Bennett D, Bischof O, Bishop C . Cellular Senescence: Defining a Path Forward. Cell. 2019; 179(4):813-827. DOI: 10.1016/j.cell.2019.10.005. View

16.

Kimura K, Matsumoto S, Harada T, Morii E, Nagatomo I, Shintani Y . ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target. Cancer Sci. 2020; 111(3):951-961. PMC: 7060486. DOI: 10.1111/cas.14303. View

17.

Phadke M, Krynetskaia N, Mishra A, Krynetskiy E . Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells. Biochem Biophys Res Commun. 2011; 411(2):409-15. PMC: 3154080. DOI: 10.1016/j.bbrc.2011.06.165. View

18.

Huo Y, Zhang K, Han S, Feng Y, Bao Y . Lymphocyte cytosolic protein 2 is a novel prognostic marker in lung adenocarcinoma. J Int Med Res. 2021; 49(11):3000605211059681. PMC: 8649447. DOI: 10.1177/03000605211059681. View

19.

Chang Y, Chan Y, Chang W, Lin Y, Yang C, Su C . Feedback regulation of ALDOA activates the HIF-1α/MMP9 axis to promote lung cancer progression. Cancer Lett. 2017; 403:28-36. DOI: 10.1016/j.canlet.2017.06.001. View

20.

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R . Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018; 36(5):411-420. PMC: 6700744. DOI: 10.1038/nbt.4096. View