Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Screening of Hub Gene Targets for Lung Cancer via Microarray Data

Author(s): Chang Su*, Wen-Xiu Liu, Li-Sha Wu, Tian-Jian Dong and Jun-Feng Liu

Volume 24, Issue 2, 2021

Published on: 08 August, 2020

Page: [269 - 285] Pages: 17

DOI: 10.2174/1386207323666200808172631

Price: $65

Abstract

Background: Lung cancer is one of the malignancies exhibiting the fastest increase in morbidity and mortality, but the cause is not clearly understood. The goal of this investigation was to screen and identify relevant biomarkers of lung cancer.

Methods: Publicly available lung cancer data sets, including GSE40275 and GSE134381, were obtained from the GEO database. The repeatability test for data was done by principal component analysis (PCA), and a GEO2R was performed to screen differentially expressed genes (DEGs), which were all subjected to enrichment analysis. Protein-protein interactions (PPIs), and the significant module and hub genes were identified via Cytoscape. Expression and correlation analysis of hub genes was done, and an overall survival analysis of lung cancer was performed. A receiver operating characteristic (ROC) curve analysis was performed to test the sensitivity and specificity of the identified hub genes for diagnosing lung cancer.

Results: The repeatability of the two datasets was good and 115 DEGs and 10 hub genes were identified. Functional analysis revealed that these DEGs were associated with cell adhesion, the extracellular matrix, and calcium ion binding. The DEGs were mainly involved with ECM-receptor interaction, ABC transporters, cell-adhesion molecules, and the p53 signaling pathway. Ten genes including COL1A2, POSTN, DSG2, CDKN2A, COL1A1, KRT19, SLC2A1, SERPINB5, DSC3, and SPP1 were identified as hub genes through module analysis in the PPI network. Lung cancer patients with high expression of COL1A2, POSTN, DSG2, CDKN2A, COL1A1, SLC2A1, SERPINB5, and SPP1 had poorer overall survival times than those with low expression (p <0.05). The CTD database showed that 10 hub genes were closely related to lung cancer. Expression of POSTN, DSG2, CDKN2A, COL1A1, SLC2A1, SERPINB5, and SPP1 was also associated with a diagnosis of lung cancer (p<0.05). ROC analysis showed that SPP1 (AUC = 0.940, p = 0.000*, 95%CI = 0.930-0.973, ODT = 7.004), SLC2A1 (AUC = 0.889, p = 0.000*, 95%CI = 0.791-0.865, ODT = 7.123), CDKN2A (AUC = 0.730, p = 0.000*, 95%CI = 0.465-1.000, ODT = 6.071) were suitable biomarkers.

Conclusion: Microarray technology represents an effective method for exploring genetic targets and molecular mechanisms of lung cancer. In addition, the identification of hub genes of lung cancer provides novel research insights for the diagnosis and treatment of lung cancer.

Keywords: Lung cancer, hub gene, differentially expressed genes, bioinformatics, overall survival, microarray data.

[1]
Ali, I.; Lone, M.N.; Al-Othman, Z.A.; Al-Warthan, A.; Sanagi, M.M. Heterocyclic scaffolds: centrality in anticancer drug development. Curr. Drug Targets, 2015, 16(7), 711-734.
[http://dx.doi.org/10.2174/1389450116666150309115922] [PMID: 25751009]
[2]
Ali, I. Nano anti-cancer drugs: pros and cons and future perspectives. Curr. Cancer Drug Targets, 2011, 11(2), 131-134.
[http://dx.doi.org/10.2174/156800911794328457] [PMID: 21062238]
[3]
Ali, I.; Alharbi, O.M.L.; Tkachev, A.; Galunin, E.; Burakov, A.; Grachev, V.A. Water treatment by new-generation graphene materials: hope for bright future. Environ. Sci. Pollut. Res. Int., 2018, 25(8), 7315-7329.
[http://dx.doi.org/10.1007/s11356-018-1315-9] [PMID: 29359248]
[4]
Ali, I. Nano drugs: novel agents for cancer chemo-therapy. Curr. Cancer Drug Targets, 2011, 11(2), 130.
[http://dx.doi.org/10.2174/156800911794328466] [PMID: 21247391]
[5]
Ali, I.; Lone, M.N.; Suhail, M.; Mukhtar, S.D.; Asnin, L. Advances in nanocarriers for anticancer drugs delivery. Curr. Med. Chem., 2016, 23(20), 2159-2187.
[http://dx.doi.org/10.2174/0929867323666160405111152] [PMID: 27048343]
[6]
Ali, I.; Haque, A.; Wani, W.A.; Saleem, K.; Al Za’abi, M. Analyses of anticancer drugs by capillary electrophoresis: a review. Biomed. Chromatogr., 2013, 27(10), 1296-1311.
[http://dx.doi.org/10.1002/bmc.2953] [PMID: 23843248]
[7]
Ali, I. Rahis-Uddin; Salim, K.; Rather, M.A.; Wani, W.A.; Haque, A. Advances in nano drugs for cancer chemotherapy. Curr. Cancer Drug Targets, 2011, 11(2), 135-146.
[http://dx.doi.org/10.2174/156800911794328493] [PMID: 21158724]
[8]
Ali, I.; Wani, W.A.; Haque, A.; Saleem, K. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. Future Med. Chem., 2013, 5(8), 961-978.
[http://dx.doi.org/10.4155/fmc.13.62] [PMID: 23682571]
[9]
Ali, I.; Wani, W.A.; Saleem, K.; Wesselinova, D. Syntheses, DNA binding and anticancer profiles of L-glutamic acid ligand and its copper(II) and ruthenium(III) complexes. Med. Chem., 2013, 9(1), 11-21.
[http://dx.doi.org/10.2174/157340613804488297] [PMID: 22741786]
[10]
Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol. Biomarkers Prev., 2016, 25(1), 16-27.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0578] [PMID: 26667886]
[11]
Meng, L.B.; Shan, M.J.; Qiu, Y.; Qi, R.; Yu, Z.M.; Guo, P.; Di, C.Y.; Gong, T. TPM2 as a potential predictive biomarker for atherosclerosis. Aging (Albany NY), 2019, 11(17), 6960-6982.
[http://dx.doi.org/10.18632/aging.102231] [PMID: 31487691]
[12]
van Zutven, L.J.; van Drunen, E.; de Bont, J.M.; Wattel, M.M.; Den Boer, M.L.; Pieters, R.; Hagemeijer, A.; Slater, R.M.; Beverloo, H.B. CDKN2 deletions have no prognostic value in childhood precursor-B acute lymphoblastic leukaemia. Leukemia, 2005, 19(7), 1281-1284.
[http://dx.doi.org/10.1038/sj.leu.2403769] [PMID: 15843818]
[13]
Ali, I.; Wani, W.A.; Khan, A.; Haque, A.; Ahmad, A.; Saleem, K.; Manzoor, N. Synthesis and synergistic antifungal activities of a pyrazoline based ligand and its copper(II) and nickel(II) complexes with conventional antifungals. Microb. Pathog., 2012, 53(2), 66-73.
[http://dx.doi.org/10.1016/j.micpath.2012.04.005] [PMID: 22575887]
[14]
El-Telbany, A.; Ma, P.C. Cancer genes in lung cancer: racial disparities: are there any? Genes Cancer, 2012, 3(7-8), 467-480.
[http://dx.doi.org/10.1177/1947601912465177] [PMID: 23264847]
[15]
Yang, Y.; Yin, W.; He, W.; Jiang, C.; Zhou, X.; Song, X.; Zhu, J.; Fei, K.; Cao, W.; Jiang, G. Phenotype-genotype correlation in multiple primary lung cancer patients in China. Sci. Rep., 2016, 6, 36177.
[http://dx.doi.org/10.1038/srep36177] [PMID: 27796337]
[16]
Huang, H.M.; Jiang, X.; Hao, M.L.; Shan, M.J.; Qiu, Y.; Hu, G.F.; Wang, Q.; Yu, Z.Q.; Meng, L.B.; Zou, Y.Y. Identification of biomarkers in macrophages of atherosclerosis by microarray analysis. Lipids Health Dis., 2019, 18(1), 107.
[http://dx.doi.org/10.1186/s12944-019-1056-x] [PMID: 31043156]
[17]
Zou, Y.F.; Meng, L.B.; Wang, Q.Q.; He, Z.K.; Hu, C.H.; Shan, M.J.; Wang, D.Y.; Yu, X. Identification and Functional Enrichment Analysis of Potential Diagnostic and Therapeutic Targets in Adamantinomatous Craniopharyngioma. J. Comput. Biol., 2020, 27(1), 55-68.
[http://dx.doi.org/10.1089/cmb.2019.0184] [PMID: 31424286]
[18]
Wang, Z.; Monteiro, C.D.; Jagodnik, K.M.; Fernandez, N.F.; Gundersen, G.W.; Rouillard, A.D.; Jenkins, S.L.; Feldmann, A.S.; Hu, K.S.; McDermott, M.G.; Duan, Q.; Clark, N.R.; Jones, M.R.; Kou, Y.; Goff, T.; Woodland, H.; Amaral, F.M.R.; Szeto, G.L.; Fuchs, O.; Schüssler-Fiorenza Rose, S.M.; Sharma, S.; Schwartz, U.; Bausela, X.B.; Szymkiewicz, M.; Maroulis, V.; Salykin, A.; Barra, C.M.; Kruth, C.D.; Bongio, N.J.; Mathur, V.; Todoric, R.D.; Rubin, U.E.; Malatras, A.; Fulp, C.T.; Galindo, J.A.; Motiejunaite, R.; Jüschke, C.; Dishuck, P.C.; Lahl, K.; Jafari, M.; Aibar, S.; Zaravinos, A.; Steenhuizen, L.H.; Allison, L.R.; Gamallo, P.; de Andres Segura, F.; Dae Devlin, T.; Pérez-García, V.; Ma’ayan, A. Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd. Nat. Commun., 2016, 7, 12846.
[http://dx.doi.org/10.1038/ncomms12846] [PMID: 27667448]
[19]
Ringnér, M. What is principal component analysis? Nat. Biotechnol., 2008, 26(3), 303-304.
[http://dx.doi.org/10.1038/nbt0308-303] [PMID: 18327243]
[20]
Kameshwar, A.K.; Qin, W. Metadata analysis of phanerochaete chrysosporium gene expression data identified common CAZymes encoding gene expression profiles involved in cellulose and hemicellulose degradation. Int. J. Biol. Sci., 2017, 13(1), 85-99.
[http://dx.doi.org/10.7150/ijbs.17390] [PMID: 28123349]
[21]
Szklarczyk, D.; Franceschini, A.; Wyder, S.; Forslund, K.; Heller, D.; Huerta-Cepas, J.; Simonovic, M.; Roth, A.; Santos, A.; Tsafou, K.P.; Kuhn, M.; Bork, P.; Jensen, L.J.; von Mering, C. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res., 2015, 43(Database issue), D447-D452.
[http://dx.doi.org/10.1093/nar/gku1003] [PMID: 25352553]
[22]
Smoot, M.E.; Ono, K.; Ruscheinski, J.; Wang, P.L.; Ideker, T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics, 2011, 27(3), 431-432.
[http://dx.doi.org/10.1093/bioinformatics/btq675] [PMID: 21149340]
[23]
Bader, G.D.; Hogue, C.W. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics, 2003, 4, 2.
[http://dx.doi.org/10.1186/1471-2105-4-2] [PMID: 12525261]
[24]
Ashburner, M.; Ball, C.A.; Blake, J.A.; Botstein, D.; Butler, H.; Cherry, J.M.; Davis, A.P.; Dolinski, K.; Dwight, S.S.; Eppig, J.T.; Harris, M.A.; Hill, D.P.; Issel-Tarver, L.; Kasarskis, A.; Lewis, S.; Matese, J.C.; Richardson, J.E.; Ringwald, M.; Rubin, G.M.; Sherlock, G. The Gene Ontology Consortium Gene ontology: tool for the unification of biology. Nat. Genet., 2000, 25(1), 25-29.
[http://dx.doi.org/10.1038/75556] [PMID: 10802651]
[25]
Kanehisa, M.; Furumichi, M.; Tanabe, M.; Sato, Y.; Morishima, K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res., 2017, 45(D1), D353-D361.
[http://dx.doi.org/10.1093/nar/gkw1092] [PMID: 27899662]
[26]
Maere, S.; Heymans, K.; Kuiper, M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics, 2005, 21(16), 3448-3449.
[http://dx.doi.org/10.1093/bioinformatics/bti551] [PMID: 15972284]
[27]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[28]
Zhou, Y.; Zhou, B.; Pache, L.; Chang, M.; Khodabakhshi, A.H.; Tanaseichuk, O.; Benner, C.; Chanda, S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun., 2019, 10(1), 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[29]
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.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[30]
Davis, A.P.; Grondin, C.J.; Johnson, R.J.; Sciaky, D.; King, B.L.; McMorran, R.; Wiegers, J.; Wiegers, T.C.; Mattingly, C.J. The Comparative Toxicogenomics Database: update 2017. Nucleic Acids Res., 2017, 45(D1), D972-D978.
[http://dx.doi.org/10.1093/nar/gkw838] [PMID: 27651457]
[31]
Li, J.; Wang, Y.; Xue, S.; Sun, J.; Zhang, W.; Hu, P.; Ji, L.; Mao, Z. Effective combination treatment of lung cancer cells by single vehicular delivery of siRNA and different anticancer drugs. Int. J. Nanomedicine, 2016, 11, 4609-4624.
[http://dx.doi.org/10.2147/IJN.S107345] [PMID: 27695321]
[32]
Shahadin, M.S.; Ab Mutalib, N.S.; Latif, M.T.; Greene, C.M.; Hassan, T. Challenges and future direction of molecular research in air pollution-related lung cancers. Lung Cancer, 2018, 118, 69-75.
[http://dx.doi.org/10.1016/j.lungcan.2018.01.016] [PMID: 29572006]
[33]
Tang, Q.; Zhang, H.; Kong, M.; Mao, X.; Cao, X. Hub genes and key pathways of non-small lung cancer identified using bioinformatics. Oncol. Lett., 2018, 16(2), 2344-2354.
[http://dx.doi.org/10.3892/ol.2018.8882] [PMID: 30008938]
[34]
Huang, H.; Huang, Q.; Tang, T.; Zhou, X.; Gu, L.; Lu, X.; Liu, F. Differentially expressed gene screening, biological function enrichment, and correlation with prognosis in non-small cell lung canceR. Med. Sci. Monit., 2019, 25, 4333-4341.
[http://dx.doi.org/10.12659/MSM.916962] [PMID: 31181055]
[35]
Zhang, Y.; Du, W.; Chen, Z.; Xiang, C. Upregulation of PD-L1 by SPP1 mediates macrophage polarization and facilitates immune escape in lung adenocarcinoma. Exp. Cell Res., 2017, 359(2), 449-457.
[http://dx.doi.org/10.1016/j.yexcr.2017.08.028] [PMID: 28830685]
[36]
Chiou, J.; Chang, Y.C.; Tsai, H.F.; Lin, Y.F.; Huang, M.S.; Yang, C.J.; Hsiao, M. Follistatin-like Protein 1 inhibits lung cancer metastasis by preventing proteolytic activation of osteopontin. Cancer Res., 2019, 79(24), 6113-6125.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-0842] [PMID: 31653686]
[37]
Wang, X.; Zhang, F.; Yang, X.; Xue, M.; Li, X.; Gao, Y.; Liu, L. Secreted Phosphoprotein 1 (SPP1) contributes to second-generation EGFR tyrosine kinase inhibitor resistance in non-small cell lung cancer. Oncol. Res., 2019, 27(8), 871-877.
[http://dx.doi.org/10.3727/096504018X15426271404407] [PMID: 30832751]
[38]
Wei, C.; Bajpai, R.; Sharma, H.; Heitmeier, M.; Jain, A.D.; Matulis, S.M.; Nooka, A.K.; Mishra, R.K.; Hruz, P.W.; Schiltz, G.E.; Shanmugam, M. Development of GLUT4-selective antagonists for multiple myeloma therapy. Eur. J. Med. Chem., 2017, 139, 573-586.
[http://dx.doi.org/10.1016/j.ejmech.2017.08.029] [PMID: 28837922]
[39]
Wang, K.; Chen, R.; Feng, Z.; Zhu, Y.M.; Sun, X.X.; Huang, W.; Chen, Z.N. Identification of differentially expressed genes in non-small cell lung cancer. Aging (Albany NY), 2019, 11(23), 11170-11185.
[http://dx.doi.org/10.18632/aging.102521] [PMID: 31816603]
[40]
Maki, Y.; Soh, J.; Ichimura, K.; Shien, K.; Furukawa, M.; Muraoka, T.; Tanaka, N.; Ueno, T.; Yamamoto, H.; Asano, H.; Tsukuda, K.; Toyooka, S.; Miyoshi, S. Impact of GLUT1 and Ki-67 expression on early stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification. Oncol. Rep., 2013, 29(1), 133-140.
[http://dx.doi.org/10.3892/or.2012.2087] [PMID: 23076555]
[41]
Gao, L.W.; Wang, G.L. Comprehensive bioinformatics analysis identifies several potential diagnostic markers and potential roles of cyclin family members in lung adenocarcinoma. OncoTargets Ther., 2018, 11, 7407-7415.
[http://dx.doi.org/10.2147/OTT.S171705] [PMID: 30425528]
[42]
Casula, M.; Budroni, M.; Cossu, A.; Ascierto, P.A.; Mozzillo, N.; Canzanella, S.; Muggiano, A.; Palmieri, G. The susceptibility CDKN2 locus may have a role on prognosis of melanoma patients. Ann. Oncol., 2010, 21(6), 1379-1380.
[http://dx.doi.org/10.1093/annonc/mdq056] [PMID: 20231302]
[43]
Scalise, M.; Pochini, L.; Galluccio, M.; Console, L.; Indiveri, C. Glutamine transport and mitochondrial metabolism in cancer cell growth. Front. Oncol., 2017, 7, 306.
[http://dx.doi.org/10.3389/fonc.2017.00306] [PMID: 29376023]
[44]
Liang, Y.; Li, W.W.; Yang, B.W.; Tao, Z.H.; Sun, H.C.; Wang, L.; Xia, J.L.; Qin, L.X.; Tang, Z.Y.; Fan, J.; Wu, W.Z. Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma. Int. J. Cancer, 2012, 130(8), 1745-1754.
[http://dx.doi.org/10.1002/ijc.26166] [PMID: 21544813]
[45]
Jeong, E.H.; Lee, T.G.; Ko, Y.J.; Kim, S.Y.; Kim, H.R.; Kim, H.; Kim, C.H. Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells. Cell Oncol. (Dordr.), 2018, 41(6), 663-675.
[http://dx.doi.org/10.1007/s13402-018-0404-6] [PMID: 30178167]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy