The purpose of this work was to explore the systematic molecular mechanism of lung adenocarcinoma and gain a deeper insight into it.
Methods
Comprehensive bioinformatics methods were applied. Initially, significant differentially expressed genes (DEGs) were analyzed from the Affymetrix microarray data (GSE27262) deposited in the Gene Expression Omnibus (GEO). Subsequently, gene ontology (GO) analysis was performed using online Database for Annotation, Visualization and Integration Discovery (DAVID) software. Finally, significant pathway crosstalk was investigated based on the information derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.
Results
According to our results, the N-terminal globular domain of the type X collagen (COL10A1) gene and transmembrane protein 100 (TMEM100) gene were identified to be the most significant DEGs in tumor tissue compared with the adjacent normal tissues. The main GO categories were biological process, cellular component and molecular function. In addition, the crosstalk was significantly different between non-small cell lung cancer pathways and inositol phosphate metabolism pathway, focal adhesion signal pathway, vascular smooth muscle contraction signal pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and calcium signaling pathway in tumor.
Conclusions
Dysfunctional genes and pathways may play key roles in the progression and development of lung adenocarcinoma. Our data provide a systematic perspective for understanding this mechanism and may be helpful in discovering an effective treatment for lung adenocarcinoma.
DovalD.C.AzamS.BatraU.Epidermal growth factor receptor mutation in lung adenocarcinoma in India: a single center study. J Carcinog.2013; 12(1): 12.
2.
TravisW.D.Pathology and genetics: tumours of the lung, pleura, thymus, and heart. Vol. 7. Lyon: IARC Press; 2004.
3.
KleihuesP.SobinL.H.World Health Organization classification of tumors. Cancer.2000; 88(12): 2887–2887.
4.
CouraudS.ZalcmanG.MilleronB.MorinF.SouquetP.J.Lung cancer in never smokers: a review. Eur J Cancer.2012; 48(9): 1299–1311.
5.
MiuraK.BowmanE.D.SimonR.Laser capture microdissection and microarray expression analysis of lung adenocarcinoma reveals tobacco smoking- and prognosis-related molecular profiles. Cancer Res.2002; 62(11): 3244–3250.
6.
WynderE.L.GrahamE.A.Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of six hundred and eighty-four proved cases. J Am Med Assoc.1950; 143(4): 329–336.
7.
AhrendtS.A.DeckerP.A.AlawiE.A.Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer.2001; 92(6): 1525–1530.
8.
KenfieldS.A.WeiE.K.StampferM.J.RosnerB.A.ColditzG.A.Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control.2008; 17(3): 198–204.
9.
HarrisN.JaffeE.SteinH.VardimanJ.World Health Organization classification of tumours: pathology and genetics: tumours of haematopoietic and lymphoid tissues.Lyon: IARC Press; 2001.
SuJ.L.ShihJ.Y.YenM.L.Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res.2004; 64(2): 554–564.
12.
ChengC.C.YangS.M.HuangC.Y.ChenJ.C.ChangW.M.HsuS.L.Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother Pharmacol.2005; 55(6): 531–540.
13.
XueX.YinZ.LuY.The joint effect of hOGG1, APE1, and ADPRT polymorphisms and cooking oil fumes on the risk of lung adenocarcinoma in Chinese non-smoking females. PLoS ONE.2013; 8(8): e71157.
14.
LinM.T.LeeR.C.YangP.C.HoF.M.KuoM.L.Cyclooxygenase-2 inducing Mcl-1-dependent survival mechanism in human lung adenocarcinoma CL1.0 cells: involvement of phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem.2001; 276(52): 48997–49002.
15.
BostF.McKayR.DeanN.MercolaD.The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells. J Biol Chem.1997; 272(52): 33422–33429.
16.
SunagaN.KohnoT.KolligsF.T.FearonE.R.SaitoR.YokotaJ.Constitutive activation of the Wnt signaling pathway by CTNNB1 (β-catenin) mutations in a subset of human lung adenocarcinoma. Genes Chromosomes Cancer.2001; 30(3): 316–321.
17.
WeiT.Y.JuanC.C.HisaJ.Y.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.2012; 103(9): 1640–1650.
18.
DavisS.MeltzerP.S.GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics.2007; 23(14): 1846–1847.
19.
DibounI.WernischL.OrengoC.A.KoltzenburgM.Microarray analysis after RNA amplification can detect pronounced differences in gene expression using limma. BMC Genomics.2006; 7(1): 252.
20.
AshburnerM.BallC.A.BlakeJ.A.; The Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat Genet.2000; 25(1): 25–29.
21.
HuangD.W.ShermanB.T.TanQ.The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol.2007; 8(9): R183.
22.
BenjaminiY.HochbergY.Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol.1995; 57: 289–300.
LiuZ.P.WangY.ZhangX.S.ChenL.Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains. BMC Syst Biol.2010; 4(Suppl 2): S11.
25.
SmootM.E.OnoK.RuscheinskiJ.WangP.L.IdekerT.Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics.2011; 27(3): 431–432.
26.
CathcartM.C.GatelyK.CumminsR.Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer. Biochim Biophys Acta.2014; 1842(5): 747–755.
27.
MacchiariniP.FontaniniG.HardinM.J.SquartiniF.AngelettiC.A.Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet.1992; 340(8812): 145–146.
28.
FontaniniG.VignatiS.BoldriniL.Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res.1997; 3(6): 861–865.
29.
ChapmanK.B.PrendesM.J.SternbergH.COL10A1 expression is elevated in diverse solid tumor types and is associated with tumor vasculature. Future Oncol.2012; 8(8): 1031–1040.
30.
EisenmanS.T.GibbonsS.J.SinghR.D.Distribution of TMEM100 in the mouse and human gastrointestinal tract: a novel marker of enteric nerves. Neuroscience.2013; 240: 117–128.
31.
FrullantiE.ColomboF.FalvellaF.S.Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue. Int J Cancer.2012; 131(5): E643–E648.
32.
SinghR.P.AgarwalR.Prostate cancer and inositol hexaphosphate: efficacy and mechanisms. Anticancer Res.2005; 25(4): 2891–2903.
33.
ShamsuddinA.M.VucenikI.ColeK.E.IP6: a novel anti-cancer agent. Life Sci.1997; 61(4): 343–354.
34.
ShamsuddinA.K.VucenikI.IP6 & inositol in cancer prevention and therapy. Current Cancer Therapy Reviews.2005; 1(3): 259–269.
35.
VucenikI.ShamsuddinA.M.Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic. J Nutr.2003; 133(11)(Suppl 1): 3778S–3784S.
36.
BatenA.UllahA.TomazicV.J.ShamsuddinA.M.Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression. Carcinogenesis.1989; 10(9): 1595–1598.
37.
PandiriA.R.SillsR.C.ZiglioliV.Differential transcriptomic analysis of spontaneous lung tumors in B6C3F1 mice: comparison to human non-small cell lung cancer. Toxicol Pathol.2012; 40(8): 1141–1159.
38.
McLeanG.W.CarragherN.O.AvizienyteE.EvansJ.BruntonV.G.FrameM.C.The role of focal-adhesion kinase in cancer: a new therapeutic opportunity. Nat Rev Cancer.2005; 5(7): 505–515.
39.
ZhaoJ.GuanJ.L.Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev.2009; 28(1-2): 35–49.
40.
StaffordL.J.XiaC.MaW.CaiY.LiuM.Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res.2002; 62(19): 5399–5404.
41.
KerstenS.DesvergneB.WahliW.Roles of PPARs in health and disease. Nature.2000; 405(6785): 421–424.
42.
MartiniB.[Lung cancer: epidemiology, prognosis and therapy] [article in German]. Med Monatsschr Pharm.2006; 29(6): 217–221.
43.
PanigrahyD.SingerS.ShenL.Q.PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest.2002; 110(7): 923–932.
44.
CoplandJ.A.MarlowL.A.KurakataS.Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via P21WAF1/CIP1. Oncogene.2006; 25(16): 2304–2317.
45.
PiliR.KruszewskiM.P.HagerB.W.LantzJ.CarducciM.A.Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res.2001; 61(4): 1477–1485.
46.
YuJ.QiaoL.ZimmermannL.Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo.Hepatology.2006; 43(1): 134–143.
47.
YehS.L.YehC.L.ChanS.T.ChuangC.H.Plasma rich in quercetin metabolites induces G2/M arrest by upregulating PPAR-y expression in human A549 lung cancer cells. Planta Med.2011; 77(10): 992–998.
48.
HanE.J.ImC.N.ParkS.H.MoonE.Y.HongS.H.Combined treatment with peroxisome proliferator-activated receptor (PPAR) gamma ligands and gamma radiation induces apoptosis by PPARγ-independent up-regulation of reactive oxygen species-induced deoxyribonucleic acid damage signals in non-small cell lung cancer cells. Int J Radiat Oncol Biol Phys.2013; 85(5): e239–e248.
49.
ChangY.S.LeeL.C.SunF.C.ChaoC.C.FuH.W.LaiY.K.Involvement of calcium in the differential induction of heat shock protein 70 by heat shock protein 90 inhibitors, geldanamycin and radicicol, in human non-small cell lung cancer H460 cells. J Cell Biochem.2006; 97(1): 156–165.
50.
SherbetG.V.LakshmiM.S.S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer Res.1998; 18(4A): 2415–2421.
51.
YangH.ZhangQ.HeJ.LuW.Regulation of calcium signaling in lung cancer. J Thorac Dis.2010; 2(1): 52–56.
52.
SomlyoA.V.BondM.SomlyoA.P.ScarpaA.Inositol trisphosphate-induced calcium release and contraction in vascular smooth muscle. Proc Natl Acad Sci USA.1985; 82(15): 5231–5235.
53.
BanerjeeS.SenguptaK.DharK.Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol Carcinog.2006; 45(11): 871–880.
