Identification of key biomarkers and potential molecular mechanisms in lung cancer by bioinformatics analysis

Lung cancer is one of the most widespread neoplasms worldwide. To identify the key biomarkers in its carcinogenesis and development, the mRNA microarray datasets GSE102287, GSE89047, GSE67061 and GSE74706 were obtained from the Gene Expression Omnibus database. GEO2R was used to identify the differentially expressed genes (DEGs) in lung cancer. The Database for Annotation, Visualization and Integrated Discovery was used to analyze the functions and pathways of the DEGs, while the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape were used to obtain the protein-protein interaction (PPI) network. Kaplan Meier curves were used to analyze the effect of the hub genes on overall survival (OS). Module analysis was completed using Molecular Complex Detection in Cytoscape, and one co-expression network of these significant genes was obtained with cBioPortal. A total of 552 DEGs were identified among the four microarray datasets, which were mainly enriched in ‘cell proliferation’, ‘cell growth’, ‘cell division’, ‘angiogenesis’ and ‘mitotic nuclear division’. A PPI network, composed of 44 nodes and 886 edges, was constructed, and its significant module had 16 hub genes in the whole network: Opa interacting protein 5, exonuclease 1, PCNA clamp-associated factor, checkpoint kinase 1, hyaluronan-mediated motility receptor, maternal embryonic leucine zipper kinase, non-SMC condensin I complex subunit G, centromere protein F, BUB1 mitotic checkpoint serine/threonine kinase, cyclin A2, thyroid hormone receptor interactor 13, TPX2 microtubule nucleation factor, nucleolar and spindle associated protein 1, kinesin family member 20A, aurora kinase A and centrosomal protein 55. Survival analysis of these hub genes revealed that they were markedly associated with poor OS in patients with lung cancer. In summary, the hub genes and DEGs delineated in the research may aid the identification of potential targets for diagnostic and therapeutic strategies in lung cancer.

[1]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[2]  Jian-zhong Wu,et al.  Overexpression of KIF20A confers malignant phenotype of lung adenocarcinoma by promoting cell proliferation and inhibiting apoptosis , 2018, Cancer medicine.

[3]  Jinpu Yu,et al.  Identification of hub genes with prognostic values in gastric cancer by bioinformatics analysis , 2018, World Journal of Surgical Oncology.

[4]  A. Lánczky,et al.  Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets , 2018, Scientific Reports.

[5]  Man Kong,et al.  Hub genes and key pathways of non-small lung cancer identified using bioinformatics , 2018, Oncology letters.

[6]  Jing Gao,et al.  Identification of candidate biomarkers and pathways associated with SCLC by bioinformatics analysis , 2018, Molecular medicine reports.

[7]  Wei Li,et al.  Thyroid hormone receptor interactor 13 (TRIP13) overexpression associated with tumor progression and poor prognosis in lung adenocarcinoma. , 2018, Biochemical and biophysical research communications.

[8]  J. Qin,et al.  Correlations Between mRNA Levels of Centrosomal Protein 55 (CEP55) and Clinical Features of Patients with Lung Cancer , 2018, Medical science monitor : international medical journal of experimental and clinical research.

[9]  Yubo Xiao,et al.  Identification of key differentially expressed genes associated with non-small cell lung cancer by bioinformatics analyses , 2018, Molecular medicine reports.

[10]  A. Zingone,et al.  Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans , 2017, Clinical Cancer Research.

[11]  F. Gao,et al.  Targeting protein for Xenopus kinesin‐like protein 2 knockdown enhances radiation sensitivity of human lung squamous carcinoma cell , 2017, Clinical and experimental pharmacology & physiology.

[12]  K. Dalby,et al.  MELK: a potential novel therapeutic target for TNBC and other aggressive malignancies , 2017, Expert opinion on therapeutic targets.

[13]  Bin Liang,et al.  Diagnostic MicroRNA Biomarker Discovery for Non-Small-Cell Lung Cancer Adenocarcinoma by Integrative Bioinformatics Analysis , 2017, BioMed research international.

[14]  Walter J Curran,et al.  Lung cancer: current therapies and new targeted treatments , 2017, The Lancet.

[15]  P. Bunn Karnofsky Award 2016: A Lung Cancer Journey, 1973 to 2016. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Michael Thomas,et al.  AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients , 2017, International journal of oncology.

[17]  R. Siebert,et al.  Downregulation of the TGFβ Pseudoreceptor BAMBI in Non-Small Cell Lung Cancer Enhances TGFβ Signaling and Invasion. , 2016, Cancer research.

[18]  Yusuke Nakamura,et al.  Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer , 2016, Oncotarget.

[19]  Lantao Zhao,et al.  Identification of potential therapeutic targets for lung cancer by bioinformatics analysis , 2015, Molecular medicine reports.

[20]  Yan Pan,et al.  KIAA0101 is associated with human renal cell carcinoma proliferation and migration induced by erythropoietin , 2015, Oncotarget.

[21]  Jing-Gung Chung,et al.  Curcumin alters gene expression-associated DNA damage, cell cycle, cell survival and cell migration and invasion in NCI-H460 human lung cancer cells in vitro. , 2015, Oncology reports.

[22]  Jichun Liu,et al.  Genetic risk of lung cancer associated with a single nucleotide polymorphism from EXO1: a meta analysis. , 2015, International journal of clinical and experimental medicine.

[23]  J. Brooks,et al.  NUSAP1 expression is upregulated by loss of RB1 in prostate cancer cells , 2015, The Prostate.

[24]  Yu Wang,et al.  MiR-195 suppresses non-small cell lung cancer by targeting CHEK1 , 2015, Oncotarget.

[25]  F. Cappuzzo,et al.  First-line crizotinib versus chemotherapy in ALK-positive lung cancer. , 2014, The New England journal of medicine.

[26]  Davide Heller,et al.  STRING v10: protein–protein interaction networks, integrated over the tree of life , 2014, Nucleic Acids Res..

[27]  Li-hua Shang,et al.  Newly identified biomarkers for detecting circulating tumor cells in lung adenocarcinoma. , 2014, The Tohoku journal of experimental medicine.

[28]  S. Fan,et al.  Thoc1 inhibits cell growth via induction of cell cycle arrest and apoptosis in lung cancer cells. , 2014, Molecular medicine reports.

[29]  Mariano J. Alvarez,et al.  Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. , 2014, Cancer cell.

[30]  Yan Wang,et al.  Expression of Opa interacting protein 5 (OIP5) is associated with tumor stage and prognosis of clear cell renal cell carcinoma. , 2013, Acta histochemica.

[31]  Yan Liu,et al.  [Expression of Nusap1 in the surgical margins of hepatocellular carcinoma and its association with early recurrence]. , 2013, Nan fang yi ke da xue xue bao = Journal of Southern Medical University.

[32]  C. Powell,et al.  Molecular biology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. , 2013, Chest.

[33]  Leitai Shi,et al.  Elevated KIAA0101 expression is a marker of recurrence in human gastric cancer , 2013, Cancer science.

[34]  Xiaojun Zhao,et al.  Combination analysis of Bub1 and Mad2 expression in endometrial cancer: act as a prognostic factor in endometrial cancer , 2013, Archives of Gynecology and Obstetrics.

[35]  Takashi Suzuki,et al.  BUB1 Immunolocalization in Breast Carcinoma: Its Nuclear Localization as a Potent Prognostic Factor of the Patients , 2013, Hormones and Cancer.

[36]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[37]  H. Shin,et al.  Frequent Amplification of CENPF, GMNN and CDK13 Genes in Hepatocellular Carcinomas , 2012, PloS one.

[38]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[39]  T. Mok,et al.  Personalized medicine in lung cancer: what we need to know , 2011, Nature Reviews Clinical Oncology.

[40]  Y. Shim,et al.  A functional single nucleotide polymorphism at the promoter region of cyclin A2 is associated with increased risk of colon, liver, and lung cancers , 2011, Cancer.

[41]  G. Scagliotti,et al.  Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation , 2011, Journal of Translational Medicine.

[42]  Wei Zhang,et al.  Genetic and epigenetic changes in lung carcinoma and their clinical implications , 2011, Modern Pathology.

[43]  Seon-Young Kim,et al.  OIP5 is a highly expressed potential therapeutic target for colorectal and gastric cancers. , 2010, BMB reports.

[44]  D. Bau,et al.  Lung cancer susceptibility and genetic polymorphisms of Exo1 gene in Taiwan. , 2009, Anticancer research.

[45]  Brad T. Sherman,et al.  The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists , 2007, Genome Biology.

[46]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[47]  Martin Kuiper,et al.  BiNGO: a Cytoscape plugin to assess overrepresentation of Gene Ontology categories in Biological Networks , 2005, Bioinform..

[48]  J. Mendell MicroRNAs: Critical Regulators of Development, Cellular Physiology and Malignancy , 2005, Cell cycle.

[49]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[50]  Gary D Bader,et al.  BMC Bioinformatics Methodology article Statistical significance for hierarchical clustering in genetic association and microarray expression studies , 2003 .

[51]  S. Nomoto,et al.  Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. , 2001, Cancer letters.

[52]  Y. Oshika,et al.  P-glycoprotein-mediated acquired multidrug resistance of human lung cancer cells in vivo. , 1996, British Journal of Cancer.

[53]  Chao Gao,et al.  Non-SMC Condensin I Complex, Subunit G (NCAPG) is a Novel Mitotic Gene Required for Hepatocellular Cancer Cell Proliferation and Migration. , 2018, Oncology research.

[54]  Jia Wei,et al.  Tanshinones suppress AURKA through up-regulation of miR-32 expression in non-small cell lung cancer , 2015 .

[55]  C. Powell,et al.  Molecular Biology of Lung Cancer Diagnosis and Management of Lung Cancer , 3 rd ed : American College of Chest Physicians , 2013 .

[56]  Tatsuya Kato,et al.  Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients. , 2012, Lung cancer.

[57]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[58]  Minoru Kanehisa,et al.  The KEGG database. , 2002, Novartis Foundation symposium.