Identification of differentially expressed protein‑coding genes in lung adenocarcinomas

Wang,Luyao; Li,Shicheng; Wang,Yuanyong; Tang,Zhenxue; Liu,Chaolong; Jiao,Wenjie; Liu,Jia

doi:10.3892/etm.2019.8300

Identification of differentially expressed protein‑coding genes in lung adenocarcinomas

Authors:
- Luyao Wang
- Shicheng Li
- Yuanyong Wang
- Zhenxue Tang
- Chaolong Liu
- Wenjie Jiao
- Jia Liu
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Affiliations: Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong 266000, P.R. China, Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
Published online on: December 6, 2019 https://doi.org/10.3892/etm.2019.8300
Pages: 1103-1111

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Abstract

Lung adenocarcinoma accounts for a high proportion of lung cancers. Though efforts have been made to develop new and effective treatments for this disease, the mortality rate remains high. Gene expression microarrays facilitate the study of lung cancer at the molecular level. The present study aimed to detect differentially expressed protein‑coding genes to identify novel biomarkers and therapeutic targets for lung adenocarcinoma. Aberrations in gene expression in lung adenocarcinoma were determined by analysis of mRNA microarray datasets from the Gene Expression Omnibus database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein‑protein interaction (PPI) networks and statistical analysis were used to identify the biological functions of the differentially expressed genes (DEGs). The results of the bioinformatics analysis were subsequently validated using reverse transcription‑quantitative PCR. A total of 303 DEGs were identified in lung adenocarcinomas, and they were enriched in a number of cancer‑associated GO terms and KEGG pathways. DNA topoisomerase 2 α (TOP2A), cell division cycle protein homolog 20 (CDC20), mitotic checkpoint serine/threonine protein kinase BUB1 (BUB1) and mitotic spindle assembly checkpoint protein MAD2A (MAD2L1) exhibited the highest degree of interaction in the PPI network. Survival analysis performed using Kaplan‑Meier curves and Cox regression indicated that these four genes were all significantly associated with the survival of patients with lung adenocarcinomas. In conclusion, TOP2A, CDC20, BUB1 and MAD2L1 may be key protein‑coding genes that may serve as biomarkers and therapeutic targets in lung adenocarcinomas.

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1	Centers for Disease Control and Prevention. Lung Cancer Statistics. simplecdc.gov/cancer/lung/statistics/index.htmMarch 26–2014
2	Jakobsen E, Rasmussen TR and Green A: Mortality and survival of lung cancer in Denmark: Results from the Danish lung cancer group 2000–2012. Acta Oncol. 55 (Suppl 2):S2–S9. 2016. View Article : Google Scholar
3	Richards TB, Henley SJ, Puckett MC, Weir HK, Huang B, Tucker TC and Allemani C: Lung cancer survival in the United States by race and stage (2001–2009): Findings from the CONCORD-2 study. Cancer. 123 (Suppl 24):S5079–S5099. 2017. View Article : Google Scholar
4	Travis WD: Pathology of lung cancer. Clin Chest Med. 32:669–692. 2011. View Article : Google Scholar : PubMed/NCBI
5	Reck M, Heigener DF, Mok T, Soria JC and Rabe KF: Management of non-small-cell lung cancer: Recent developments. Lancet. 382:709–719. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
7	Liang Y, Ma YY, Li LL, Shen XY, Xin T, Zhao YW and Ma R: Effect of long non-coding RNA LINC01116 on biological behaviors of non-small cell lung cancer cells via the hippo signaling pathway. J Cell Biochem. 1192018.DOI: 10.1002/jcb.26711.
8	Barrett T and Edgar R: Mining microarray data at NCBI's Gene Expression Omnibus (GEO)*. Methods Mol Biol. 338:175–190. 2006.PubMed/NCBI
9	Edgar R, Domrachev M and Lash AE: Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30:207–210. 2002. View Article : Google Scholar : PubMed/NCBI
10	Wei TY, Juan CC, Hisa JY, Su LJ, Lee YC, Chou HY, Chen JM, Wu YC, Chiu SC, Hsu CP, et al: Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. Cancer Sci. 103:1640–1650. 2012. View Article : Google Scholar : PubMed/NCBI
11	Wei TY, Hsia JY, Chiu SC, Su LJ, Juan CC, Lee YC, Chen JM, Chou HY, Huang JY, Huang HM and Yu CT: Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis. Cell Signal. 26:2940–2950. 2014. View Article : Google Scholar : PubMed/NCBI
12	Beer DG, Kardia SL, Huang CC, Giordano TJ, Levin AM, Misek DE, Lin L, Chen G, Gharib TG, Thomas DG, et al: Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 8:816–824. 2002. View Article : Google Scholar : PubMed/NCBI
13	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
14	Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, et al: Proteomics. Tissue-based map of the human proteome. Science. 347:12604192015. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Lemjabbar-Alaoui H, Hassan OU, Yang YW and Buchanan P: Lung cancer: Biology and treatment options. Biochim Biophys Acta. 1856:189–210. 2015.PubMed/NCBI
17	Xing Z, Chu C, Chen L and Kong X: The use of Gene Ontology terms and KEGG pathways for analysis and prediction of oncogenes. Biochim Biophys Acta. 1860:2725–2734. 2016. View Article : Google Scholar : PubMed/NCBI
18	Wu KZ, Wang GN, Fitzgerald J, Quachthithu H, Rainey MD, Cattaneo A, Bachi A and Santocanale C: DDK dependent regulation of TOP2A at centromeres revealed by a chemical genetics approach. Nucleic Acids Res. 44:8786–8798. 2016. View Article : Google Scholar : PubMed/NCBI
19	Klintman M, Buus R, Cheang MC, Sheri A, Smith IE and Dowsett M: Changes in expression of genes representing key biologic processes after neoadjuvant chemotherapy in breast cancer, and prognostic implications in residual disease. Clin Cancer Res. 22:2405–2416. 2016. View Article : Google Scholar : PubMed/NCBI
20	Ocaña A, Pérez-Peña J, Alcaraz-Sanabria A, Sánchez-Corrales V, Nieto-Jiménez C, Templeton AJ, Seruga B, Pandiella A and Amir E: In silico analyses identify gene-sets, associated with clinical outcome in ovarian cancer: Role of mitotic kinases. Oncotarget. 7:22865–22872. 2016. View Article : Google Scholar : PubMed/NCBI
21	Chen T, Sun Y, Ji P, Kopetz S and Zhang W: Topoisomerase IIα in chromosome instability and personalized cancer therapy. Oncogene. 34:4019–4031. 2015. View Article : Google Scholar : PubMed/NCBI
22	Delgado JL, Hsieh CM, Chan NL and Hiasa H: Topoisomerases as anticancer targets. Biochem J. 475:373–398. 2018. View Article : Google Scholar : PubMed/NCBI
23	An X, Xu F, Luo R, Zheng Q, Lu J, Yang Y, Qin T, Yuan Z, Shi Y, Jiang W and Wang S: The prognostic significance of topoisomerase II alpha protein in early stage luminal breast cancer. BMC Cancer. 18:3312018. View Article : Google Scholar : PubMed/NCBI
24	Pei YF, Yin XM and Liu XQ: TOP2A induces malignant character of pancreatic cancer through activating β-catenin signaling pathway. Biochim Biophys Acta. 1864:197–207. 2018. View Article : Google Scholar
25	Lara-Gonzalez P, Westhorpe FG and Taylor SS: The spindle assembly checkpoint. Curr Biol. 22:R966–R980. 2012. View Article : Google Scholar : PubMed/NCBI
26	Raaijmakers JA, van Heesbeen RGHP, Blomen VA, Janssen LME, van Diemen F, Brummelkamp TR and Medema RH: BUB1 is essential for the viability of human cells in which the spindle assembly checkpoint is compromised. Cell Rep. 22:1424–1438. 2018. View Article : Google Scholar : PubMed/NCBI
27	Ricke RM, Jeganathan KB, Malureanu L, Harrison AM and van Deursen JM: Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression. J Cell Biol. 199:931–949. 2012. View Article : Google Scholar : PubMed/NCBI
28	Mukherjee A, Joseph C, Craze M, Chrysanthou E and Ellis IO: The role of BUB and CDC proteins in low-grade breast cancers. Lancet. 385 (Suppl 1):S722015. View Article : Google Scholar : PubMed/NCBI
29	Stahl D, Braun M, Gentles AJ, Lingohr P, Walter A, Kristiansen G and Gütgemann I: Low BUB1 expression is an adverse prognostic marker in gastric adenocarcinoma. Oncotarget. 8:76329–76339. 2017. View Article : Google Scholar : PubMed/NCBI
30	Hartwell LH, Culotti J and Reid B: Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci USA. 66:352–359. 1970. View Article : Google Scholar : PubMed/NCBI
31	Quek LS, Grasset N, Jasmen JB, Robinson KS and Bellanger S: Dual role of the anaphase promoting Complex/Cyclosome in regulating Stemness and differentiation in human primary keratinocytes. J Invest Dermatol. 138:1851–1861. 2018. View Article : Google Scholar : PubMed/NCBI
32	Kapanidou M, Curtis NL and Bolanos-Garcia VM: Cdc20: At the Crossroads between chromosome segregation and mitotic exit. Trends Biochem Sci. 42:193–205. 2017. View Article : Google Scholar : PubMed/NCBI
33	Taniguchi K, Momiyama N, Ueda M, Matsuyama R, Mori R, Fujii Y, Ichikawa Y, Endo I, Togo S and Shimada H: Targeting of CDC20 via small interfering RNA causes enhancement of the cytotoxicity of chemoradiation. Anticancer Res. 28:1559–1563. 2008.PubMed/NCBI
34	Jiang J, Jedinak A and Sliva D: Ganodermanontriol (GDNT) exerts its effect on growth and invasiveness of breast cancer cells through the down-regulation of CDC20 and uPA. Biochem Biophys Res Commun. 415:325–329. 2011. View Article : Google Scholar : PubMed/NCBI
35	Chang DZ, Ma Y, Ji B, Liu Y, Hwu P, Abbruzzese JL, Logsdon C and Wang H: Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression. J Hematol Oncol. 5:152012. View Article : Google Scholar : PubMed/NCBI
36	Choi JW, Kim Y, Lee JH and Kim YS: High expression of spindle assembly checkpoint proteins CDC20 and MAD2 is associated with poor prognosis in urothelial bladder cancer. Virchows Arch. 463:681–687. 2013. View Article : Google Scholar : PubMed/NCBI
37	Kato T, Daigo Y, Aragaki M, Ishikawa K, Sato M and Kaji M: Overexpression of CDC20 predicts poor prognosis in primary non-small cell lung cancer patients. J Surg Oncol. 106:423–430. 2012. View Article : Google Scholar : PubMed/NCBI
38	Karra H, Repo H, Ahonen I, Löyttyniemi E, Pitkänen R, Lintunen M, Kuopio T, Söderström M and Kronqvist P: Cdc20 and securin overexpression predict short-term breast cancer survival. Br J Cancer. 110:2905–2913. 2014. View Article : Google Scholar : PubMed/NCBI
39	Han Y, Jin X, Zhou H and Liu B: Identification of key genes associated with bladder cancer using gene expression profiles. Oncol Lett. 15:297–303. 2018.PubMed/NCBI
40	He X, Zhang C, Shi C and Lu Q: Meta-analysis of mRNA expression profiles to identify differentially expressed genes in lung adenocarcinoma tissue from smokers and non-smokers. Oncol Rep. 39:929–938. 2018.PubMed/NCBI
41	Wang Z, Katsaros D, Shen Y, Fu Y, Canuto EM, Benedetto C, Lu L, Chu WM, Risch HA and Yu H: Biological and clinical significance of MAD2L1 and BUB1, genes frequently appearing in expression signatures for breast cancer prognosis. PLoS One. 10:e01362462015. View Article : Google Scholar : PubMed/NCBI
42	Kato T, Daigo Y, Aragaki M, Ishikawa K, Sato M, Kondo S and Kaji M: Overexpression of MAD2 predicts clinical outcome in primary lung cancer patients. Lung Cancer. 74:124–131. 2011. View Article : Google Scholar : PubMed/NCBI
43	Asmis TR, Ding K, Seymour L, Shepherd FA, Leighl NB, Winton TL, Whitehead M, Spaans JN, Graham BC and Goss GD; National Cancer Institute of Canada Clinical Trials Group, : Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: A review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol. 26:54–59. 2008. View Article : Google Scholar : PubMed/NCBI
44	Zou ZQ, Du YY, Sui G and Xu SN: Expression of TS, RRM1, ERCC1, TUBB3 and STMN1 genes in tissues of non-small cell lung cancer and its significance in guiding postoperative adjuvant chemotherapy. Asian Pac J Cancer Prev. 16:3189–3194. 2015. View Article : Google Scholar : PubMed/NCBI