Identification and Verification of Hub Genes Associated with the Progression of Non-small Cell Lung Cancer by Integrated Analysis

Overview

Journal Front Pharmacol

Date 2022 Sep 30

PMID 36176446

Authors

Xie Mengyan

Ding Kun

Jing Xinming

Wei Yutian

Shu Yongqian

Affiliations

Soon will be listed here.

Abstract

Lung cancer is one of the most common cancers worldwide and it is the leading cause of cancer-related mortality. Despite the treatment of patients with non-small cell lung carcinoma (NSCLC) have improved, the molecular mechanisms of NSCLC are still to be further explored. Microarray datasets from the Gene Expression Omnibus (GEO) database were selected to identify the candidate genes associated with tumorigenesis and progression of non-small cell lung carcinoma. The differentially expressed genes (DEGs) were identified by GEO2R. Protein-protein interaction network (PPI) were used to screen out hub genes. The expression levels of hub genes were verified by GEPIA, Oncomine and The Human Protein Atlas (HPA) databases. Survival analysis and receiver operating characteristic (ROC) curve analysis were performed to value the importance of hub genes in NSCLC diagnosis and prognosis. ENCODE and cBioPortal were used to explore the upstream regulatory mechanisms of hub genes. Analysis on CancerSEA Tool, CCK8 assay and colony formation assay revealed the functions of hub genes in NSCLC. A total of 426 DEGs were identified, including 93 up-regulated genes and 333 down-regulated genes. And nine hub genes (CDC6, KIAA0101, CDC20, BUB1B, CCNA2, NCAPG, KIF11, BUB1 and CDK1) were found to increase with the tumorigenesis, progression and cisplatin resistance of NSCLC, especially EGFR- or KRAS-mutation driven NSCLC. Hub genes were valuable biomarkers for NSCLC, and the overexpression of hub genes led to poor survival of NSCLC patients. Function analysis showed that hub genes played roles in cell cycle and proliferation, and knockdown of hub genes significantly inhibited A549 and SPCA1 cell growth. Further exploration demonstrated that copy number alterations (CNAs) and transcription activation may account for the up-regulation of hub genes. Hub genes identified in this study provided better understanding of molecular mechanisms within tumorigenesis and progression of NSCLC, and provided potential targets for NSCLC treatment as well.

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References

Drilon A, Siena S, Ou S, Patel M, Ahn M, Lee J . Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017; 7(4):400-409. PMC: 5380583. DOI: 10.1158/2159-8290.CD-16-1237. View

Schafer J, Lehmann B, Gonzalez-Ericsson P, Marshall C, Beeler J, Redman L . Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors. Sci Transl Med. 2020; 12(534). PMC: 7427123. DOI: 10.1126/scitranslmed.aaw8275. View

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

Dummer R, Lebbe C, Atkinson V, Mandala M, Nathan P, Arance A . Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med. 2020; 26(10):1557-1563. DOI: 10.1038/s41591-020-1082-2. View

Gyorffy B, Surowiak P, Budczies J, Lanczky A . Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 2013; 8(12):e82241. PMC: 3867325. DOI: 10.1371/journal.pone.0082241. View

Zhou J, Ye J, Zhao X, Li A, Zhou J . JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway. Toxicol Appl Pharmacol. 2008; 230(1):33-40. DOI: 10.1016/j.taap.2008.01.041. View

Barrett T, Wilhite S, Ledoux P, Evangelista C, Kim I, Tomashevsky M . NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 2012; 41(Database issue):D991-5. PMC: 3531084. DOI: 10.1093/nar/gks1193. View

Roy B, Han S, Fontan A, Jema S, Joglekar A . Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling. Curr Biol. 2021; 32(1):237-247.e6. PMC: 8752509. DOI: 10.1016/j.cub.2021.10.049. View

Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P . The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2010; 39(Database issue):D561-8. PMC: 3013807. DOI: 10.1093/nar/gkq973. View

10.

Hata A, Niederst M, Archibald H, Gomez-Caraballo M, Siddiqui F, Mulvey H . Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016; 22(3):262-9. PMC: 4900892. DOI: 10.1038/nm.4040. View

11.

Wang L, Zhang J, Wan L, Zhou X, Wang Z, Wei W . Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol Ther. 2015; 151:141-51. PMC: 4457591. DOI: 10.1016/j.pharmthera.2015.04.002. View

12.

Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K . Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007; 448(7155):811-5. DOI: 10.1038/nature06046. View

13.

Mesaros E, Ott G, Dorsey B . Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review. Expert Opin Ther Pat. 2014; 24(4):417-42. DOI: 10.1517/13543776.2014.877890. View

14.

Dearden S, Stevens J, Wu Y, Blowers D . Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-6. PMC: 3755331. DOI: 10.1093/annonc/mdt205. View

15.

Tulchinsky E, Demidov O, Kriajevska M, Barlev N, Imyanitov E . EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer. Biochim Biophys Acta Rev Cancer. 2018; 1871(1):29-39. DOI: 10.1016/j.bbcan.2018.10.003. View

16.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

17.

Ercan D, Choi H, Yun C, Capelletti M, Xie T, Eck M . EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clin Cancer Res. 2015; 21(17):3913-23. PMC: 4791951. DOI: 10.1158/1078-0432.CCR-14-2789. View

18.

Haneke K, Schott J, Lindner D, Hollensen A, Damgaard C, Mongis C . CDK1 couples proliferation with protein synthesis. J Cell Biol. 2020; 219(3). PMC: 7054999. DOI: 10.1083/jcb.201906147. View

19.

Kanehisa M, Sato Y, Furumichi M, Morishima K, Tanabe M . New approach for understanding genome variations in KEGG. Nucleic Acids Res. 2018; 47(D1):D590-D595. PMC: 6324070. DOI: 10.1093/nar/gky962. View

20.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View