Identification of Key Genes Between Lung Adenocarcinoma and Lung Squamous Cell Carcinoma by Bioinformatics Analysis

doi:10.37015/AUDT.2020.200011

Abstract

Abstract:

Objective: To explore differentially expressed genes (DEGs) between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
Methods: Based on GEO database, we used R software to identify the DEGs and conducted the bioinformatics analysis to explore the molecular mechanisms of DEGs and constructed PPI network to find the key DEGs. Then we assessed the effect of the eligible key DEGs on survival in LUAD by Kaplan-Meier plotter online tool.
Results: GSE10245 was downloaded from the GEO database, which contained a total of 58 tissue samples, including 18 LUSC and 40 LUAD. We identified 784 DEGs between LUAD and LUSC. DEGs were enriched in statistical significant GO annotation 201 items and KEGG pathways 17 items. By constructed PPI network, we obtained 10 hub genes. Of which, five genes were significantly correlated with the overall survival of LUAD.
Conclusions: P2RY1, CHRM3, LPAR3, NMU, and S1PR5 may be the potential prognostic markers and therapeutic targets for LUAD.

Key words: Bioinformatics analysis; LUAD; Differentially expressed genes

Jinru Xue, MS, Yu Yang, MS, Bo Jiang, MD, Linxue Qian, MD, Xian-Quan Shi, PhD. Identification of Key Genes Between Lung Adenocarcinoma and Lung Squamous Cell Carcinoma by Bioinformatics Analysis. Advanced Ultrasound in Diagnosis and Therapy, 2020, 4(4): 335-342.

References

[1]	Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015; 10:1243-1260.
[2]	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424.
[3]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67:7-30.
[4]	Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015; 10:1243-1260.
[5]	Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11:39-51.
[6]	Vansteenkiste J, Crinò L, Dooms C, Douillard JY, Faivre-Finn C, Lim E, et al. 2nd ESMO consensus conference on lung cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. Ann Oncol 2014; 25:1462-1474.
[7]	Travis WD. Pathology of lung cancer. Clin Chest Med 2011; 32:669-692.
[8]	Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; 511:543-550.
[9]	Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489:519-525.
[10]	Tsao AS, Scagliotti GV, Bunn PA Jr, Carbone DP, Warren GW, Bai C, et al. Scientific advances in lung cancer 2015. J Thorac Oncol 2016; 11:613-638.
[11]	Bro?t P, Camilleri-Bro?t S, Zhang S, Alifano M, Bangarusamy D, Battistella M, et al. Prediction of clinical outcome in multiple lung cancer cohorts by integrative genomics: implications for chemotherapy selection. Cancer Res 2009; 69:1055-1062.
[12]	Giangreco A, Groot KR, Janes SM. Lung cancer and lung stem cells: strange bedfellows?. Am J Respir Crit Care Med 2007; 175:547-553.
[13]	Pikor LA, Ramnarine VR, Lam S, Lam WL. Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer 2013; 82:179-189.
[14]	Sato M, Shames DS, Gazdar AF, Minna JD. A translational view of the molecular pathogenesis of lung cancer. J Thorac Oncol 2007; 2:327-343.
[15]	Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542-2550.
[16]	Thatcher N, Hirsch FR, Luft AV, Szczesna A, Ciuleanu TE, Dediu M, Ramlau R, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16:763-774.
[17]	Hata A, Katakami N, Yoshioka H. How sensitive are epidermal growth factor receptor-tyrosine kinase inhibitors for squamous cell carcinoma of the lung harboring EGFR gene-sensitive mutations? J Thorac Oncol 2014; 9:e20.
[18]	Gy?rffy B, Surowiak P, Budczies J, Lánczky 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:e82241.
[19]	Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2011; 2:180.
[20]	Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM. Exosome mediated communication within the tumor microenvironment. J Control Release 2015; 219:278-294.
[21]	Sharma S, Zu?iga F, Rice GE, Perrin LC, Hooper JD, Salomon C. Tumor-derived exosomes in ovarian cancer - liquid biopsies for early detection and real-time monitoring of cancer progression. Oncotarget 2017; 8:104687-104703.
[22]	Gettins PG. Serpin structure, mechanism, and function. Chem Rev 2002; 102:4751-4804.
[23]	Chmela? J, Kotál J, Langhansová H, Kotsyfakis M. Protease inhibitors in tick saliva: the role of serpins and cystatins in tick-host-pathogen interaction. Front Cell Infect Microbiol 2017; 7:216.
[24]	Rau JC, Beaulieu LM, Huntington JA, Church FC. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost 2007; 5 Suppl 1: 102-115.
[25]	Irving JA, Ekeowa UI, Belorgey D, Haq I, Gooptu B, Miranda E, et al. The serpinopathies studying serpin polymerization in vivo. Methods Enzymol 2011; 501:421-466.
[26]	Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, et al. The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001; 276:33293-6.
[27]	Carrell RW, Read RJ. How serpins transport hormones and regulate their release. Semin Cell Dev Biol 2017; 62:133-141.
[28]	Gooptu B, Dickens JA, Lomas DA. The molecular and cellular pathology of α?-antitrypsin deficiency. Trends Mol Med 2014; 20:116-127.
[29]	Mazzoccoli G, Pazienza V, Panza A, Valvano MR, Benegiamo G, Vinciguerra M, et al. ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer. J Cancer Res Clin Oncol 2012; 138:501-511.
[30]	Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005; 17:548-558.
[31]	Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007; 7:415-428.
[32]	Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009; 119:1438-1449.
[33]	Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139:871-890.
[34]	Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331:1559-1564.
[35]	Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 2008; 14:818-829.
[36]	Mansfield KJ, Hughes JR. P2Y receptor modulation of ATP release in the urothelium. Biomed Res Int 2014; 2014:830374.
[37]	Nishi H, Arai H, Momiyama T. NCI-H295R, a human adrenal cortex-derived cell line, expresses purinergic receptors linked to Ca²⁺-mobilization/influx and cortisol secretion. PLoS One 2013; 8:e71022.
[38]	Yi X, Zhou Q, Wang C, Lin J, Liu P, Fu C. Platelet receptor Gene (P2Y12, P2Y1) and platelet glycoprotein Gene (GPIIIa) polymorphisms are associated with antiplatelet drug responsiveness and clinical outcomes after acute minor ischemic stroke. Eur J Clin Pharmacol 2017; 73:437-443.
[39]	Tan Y, Zhang T, Zhou L, Liu S, Liang C. MiR-34b-3p represses the multidrug-chemoresistance of bladder cancer cells by regulating the CCND2 and P2RY1 genes. Med Sci Monit 2019; 25:1323-1335.
[40]	Kim IW, Han N, Kim MG, Kim T, Oh JM. Copy number variability analysis of pharmacogenes in patients with lymphoma, leukemia, hepatocellular, and lung carcinoma using the cancer genome atlas data. Pharmacogenet Genomics 2015; 25:1-7.
[41]	Shah N, Khurana S, Cheng K, Raufman JP. Muscarinic receptors and ligands in cancer. Am J Physiol Cell Physiol 2009; 296:C221-32.
[42]	Lin G, Sun L, Wang R, Guo Y, Xie C. Overexpression of muscarinic receptor 3 promotes metastasis and predicts poor prognosis in non-small-cell lung cancer. J Thorac Oncol 2014; 9:170-178.
[43]	Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 2005; 24:7443-54.
[44]	Wang Y, Li J, Wen S, Yang X, Zhang Y, Wang Z, et al. CHRM3 is a novel prognostic factor of poor prognosis in patients with endometrial carcinoma. Am J Trans Res 2015; 7:902-911.
[45]	Rani S, Corcoran C, Shiels L, Germano S, Breslin S, Madden S, et al. Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors. Cancer Res 2014; 74:3821-33.
[46]	Wu Y, McRoberts K, Berr SS, Frierson HF Jr, Conaway M, Theodorescu D. Neuromedin U is regulated by the metastasis suppressor RhoGDI2 and is a novel promoter of tumor formation, lung metastasis and cancer cachexia. Oncogene 2007; 26:765-773.
[47]	You S, Gao L. Identification of NMU as a potential gene conferring alectinib resistance in non-small cell lung cancer based on bioinformatics analyses. Gene 2018; 678:137-142.
[48]	Brindley DN. Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. J Cell Biochem 2004; 92:900-912.
[49]	Fang X, Gaudette D, Furui T, Mao M, Estrella V, Eder A, et al. Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. Ann N Y Acad Sci 2000; 905:188-208.
[50]	Shida D, Watanabe T, Aoki J, Hama K, Kitayama J, Sonoda H, et al. Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer. Lab Invest 2004; 84:1352-1362.
[51]	Hayashi M, Okabe K, Yamawaki Y, Teranishi M, Honoki K, Mori T, et al. Loss of lysophosphatidic acid receptor-3 enhances cell migration in rat lung tumor cells. Biochem Biophys Res Commun 2011; 405:450-454.
[52]	Hu WM, Li L, Jing BQ, Zhao YS, Wang CL, Feng L, et al. Effect of S1P5 on proliferation and migration of human esophageal cancer cells. World J Gastroenterol 2010; 16:1859-1866.
[53]	Novgorodov AS, El-Alwani M, Bielawski J, Obeid LM, Gudz TI. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J 2007; 21:1503-1514.
[54]	Balthasar S, Samulin J, Ahlgren H, Bergelin N, Lundqvist M, Toescu EC, et al. Sphingosine 1-phosphate receptor expression profile and regulation of migration in human thyroid cancer cells. Biochem J 2006; 398:547-556.
[55]	Huang YL, Chang CL, Tang CH, Lin YC, Ju TK, Huang WP, et al. Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells. Cell Signal 2014; 26:611-618.
[56]	Chang CL, Ho MC, Lee PH, Hsu CY, Huang WP, Lee H. S1P(5) is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells. Am J Physiol Cell Physiol 2009; 297:C451-458.