Transcriptional regulatory networks in human lung adenocarcinoma

Meng,Xiangrui; Lu,Peng; Bai,Hua; Xiao,Peng; Fan,Qingxia

doi:10.3892/mmr.2012.1034

Transcriptional regulatory networks in human lung adenocarcinoma

Authors:
- Xiangrui Meng
- Peng Lu
- Hua Bai
- Peng Xiao
- Qingxia Fan
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Affiliations: Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China, Department of Oncological Surgery, People's Hospital of Zhengzhou, Zhengzhou, P.R. China, Department of Medical Oncology, People's Hospital of Zhengzhou, Zhengzhou, P.R. China
Published online on: August 14, 2012 https://doi.org/10.3892/mmr.2012.1034
Pages: 961-966

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Abstract

Lung adenocarcinoma (AC) is the most common histological subtype of lung cancer worldwide and its absolute incidence is increasing markedly. Transcriptional regulation is one of the most fundamental processes in lung AC development. However, high-throughput functional analyses of multiple transcription factors and their target genes in lung AC are rare. Thus, the objective of our study was to interpret the mechanisms of human AC through the regulatory network using the GSE2514 microarray data. Our results identified the genes peroxisome proliferator activated receptor-γ (PPARG), CCAAT/enhancer binding protein β (CEBPB), ets variant 4 (ETV4), Friend leukemia virus integration 1 (FLI1), T-cell acute lymphocytic leukemia 1 (TAL1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) as hub nodes in the transcriptome network. Among these genes, it appears that: PPARG promotes the PPAR signaling pathway via the upregulation of lipoprotein lipase (LPL) expression, but suppresses the cell cycle pathway via downregulation of growth arrest and DNA-damage-inducible, γ (GADD45G) expression; ETV4 stimulates matrix metallopeptidase 9 (MMP9) expression to induce the bladder cancer pathway; FLI upregulates transforming growth factor, β receptor II (TGFBR2) expression to activate TGF-β signaling and upregulates cyclin D3 (CCND3) expression to promote the cell cycle pathway; NFKB1 upregulates interleukin 1, β (IL-1B) expression and initiates the prostate cancer pathway; CEBPB upregulates IL-6 expression and promotes pathways in cancer; and TAL1 promotes kinase insert domain receptor (KDR) expression to promote the TGF-β signaling pathway. This transcriptional regulation analysis may provide an improved understanding of the molecular mechanisms and potential therapeutic targets in the treatment of lung AC.

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1	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar
2	Travis WD, Travis LB and Devesa SS: Lung cancer. Cancer. 75(Suppl 1): 191–202. 1995. View Article : Google Scholar : PubMed/NCBI
3	Riely GJ, Kris MG, Rosenbaum D, et al: Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 14:5731–5734. 2008. View Article : Google Scholar : PubMed/NCBI
4	Marks JL, Broderick S, Zhou Q, et al: Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 3:111–116. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kosaka T, Yatabe Y, Onozato R, Kuwano H and Mitsudomi T: Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thorac Oncol. 4:22–29. 2009. View Article : Google Scholar : PubMed/NCBI
6	Gill RK, Yang SH, Meerzaman D, et al: Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene. 30:3784–3791. 2011. View Article : Google Scholar : PubMed/NCBI
7	Ding L, Getz G, Wheeler DA, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 455:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
8	Gao SP, Mark KG, Leslie K, et al: Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 117:3846–3856. 2007. View Article : Google Scholar : PubMed/NCBI
9	Hiramatsu M, Ninomiya H, Inamura K, et al: Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. Lung Cancer. 70:94–102. 2010. View Article : Google Scholar : PubMed/NCBI
10	Stearman RS, Dwyer-Nield L, Zerbe L, et al: Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol. 167:1763–1775. 2005. View Article : Google Scholar : PubMed/NCBI
11	Wachi S, Yoneda K and Wu R: Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues. Bioinformatics. 21:4205–4208. 2005. View Article : Google Scholar : PubMed/NCBI
12	Smyth GK: Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 3:Article 32004.
13	Irizarry RA, Hobbs B, Collin F, et al: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 4:249–264. 2003. View Article : Google Scholar
14	Wingender E: The TRANSFAC project as an example of framework technology that supports the analysis of genomic regulation. Brief Bioinform. 9:326–332. 2008. View Article : Google Scholar : PubMed/NCBI
15	Jiang C, Xuan Z, Zhao F and Zhang MQ: TRED: a transcriptional regulatory element database, new entries and other development. Nucleic Acids Res. 35:D137–D140. 2007. View Article : Google Scholar : PubMed/NCBI
16	Kanehisa M: The KEGG database (Review). Novartis Found Symp. 247:91–101. 2002. View Article : Google Scholar
17	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009.PubMed/NCBI
18	Chang TH and Szabo E: Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor γ in non-small cell lung cancer. Cancer Res. 60:1129–1138. 2000.
19	Theocharis S, Kanelli H, Politi E, et al: Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade. Lung Cancer. 36:249–255. 2002. View Article : Google Scholar : PubMed/NCBI
20	Keshamouni VG, Reddy RC, Arenberg DA, et al: Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene. 23:100–108. 2004.
21	Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E and Cox LS: Characterisation of the interaction between PCNA and Gadd45. Oncogene. 10:2427–2433. 1995.PubMed/NCBI
22	Zhan Q, Antinore MJ, Wang XW, et al: Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene. 18:2892–2900. 1999. View Article : Google Scholar : PubMed/NCBI
23	Bruemmer D, Yin F, Liu J, et al: Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by peroxisome proliferator-activated receptor γ in vascular smooth muscle cells. Circ Res. 93:e38–e47. 2003.
24	Na YK, Lee SM, Hong HS, Kim JB, Park JY and Kim DS: Hypermethylation of growth arrest DNA-damage-inducible gene 45 in non-small cell lung cancer and its relationship with clinicopathologic features. Mol Cells. 30:89–92. 2010. View Article : Google Scholar : PubMed/NCBI
25	Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al: PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15:5336–5348. 1996.PubMed/NCBI
26	Li L, Beauchamp MC and Renier G: Peroxisome proliferator-activated receptor alpha and gamma agonists upregulate human macrophage lipoprotein lipase expression. Atherosclerosis. 165:101–110. 2002. View Article : Google Scholar
27	Kuemmerle NB, Rysman E, Lombardo PS, et al: Lipoprotein lipase links dietary fat to solid tumor cell proliferation. Mol Cancer Ther. 10:427–436. 2011. View Article : Google Scholar : PubMed/NCBI
28	Cerne D, Zitnik IP and Sok M: Increased fatty acid synthase activity in non-small cell lung cancer tissue is a weaker predictor of shorter patient survival than increased lipoprotein lipase activity. Arch Med Res. 41:405–409. 2010. View Article : Google Scholar
29	Shindoh M, Higashino F and Kohgo T: E1AF, an ets-oncogene family transcription factor (Review). Cancer Lett. 216:1–8. 2004. View Article : Google Scholar : PubMed/NCBI
30	Hiroumi H, Dosaka-Akita H, Yoshida K, et al: Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: Its relevance in cell motility and invasion. Int J Cancer. 93:786–791. 2001. View Article : Google Scholar : PubMed/NCBI
31	Higashino F, Yoshida K, Noumi T, Seiki M and Fujinaga K: Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters. Oncogene. 10:1461–1463. 1995.PubMed/NCBI
32	Keld R, Guo B, Downey P, Gulmann C, Ang YS and Sharrocks AD: The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma. Mol Cancer. 9:3132010. View Article : Google Scholar : PubMed/NCBI
33	Truong A and Ben-David Y: The role of Fli-1 in normal cell function and malignant transformation (Review). Oncogene. 19:6482–6489. 2000. View Article : Google Scholar : PubMed/NCBI
34	May WA, Arvand A, Thompson AD, Braun BS, Wright M and Denny CT: EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic. Nat Genet. 17:495–497. 1997. View Article : Google Scholar : PubMed/NCBI
35	Thompson AD, Teitell MA, Arvand A and Denny CT: Divergent Ewing’s sarcoma EWS/ETS fusions confer a common tumorigenic phenotype on NIH3T3 cells. Oncogene. 18:5506–5513. 1999.
36	Im YH, Kim HT, Lee C, et al: EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor β type II receptor gene. Cancer Res. 60:1536–1540. 2000.PubMed/NCBI
37	Hahm KB, Cho K, Lee C, et al: Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet. 23:222–227. 1999.
38	Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V and Dei Tos AP: Utility of the immunohistochemical detection of FLI-1 expression in round cell and vascular neoplasm using a monoclonal antibody. Mod Pathol. 17:547–552. 2004. View Article : Google Scholar : PubMed/NCBI
39	Pereira R, Quang CT, Lesault I, Dolznig H, Beug H and Ghysdael J: FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene. 18:1597–1608. 1999. View Article : Google Scholar : PubMed/NCBI
40	Grumont RJ, Fecondo J and Gerondakis S: Alternate RNA splicing of murine nfkb1 generates a nuclear isoform of the p50 precursor NF-kappa B1 that can function as a transactivator of NF-kappa B-regulated transcription. Mol Cell Biol. 14:8460–8470. 1994.PubMed/NCBI
41	Wharry CE, Haines KM, Carroll RG and May MJ: Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells. Cancer Biol Ther. 8:1567–1576. 2009. View Article : Google Scholar : PubMed/NCBI
42	Hiscott J, Marois J, Garoufalis J, et al: Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol. 13:6231–6240. 1993.PubMed/NCBI
43	Zienolddiny S, Ryberg D, Maggini V, Skaug V, Canzian F and Haugen A: Polymorphisms of the interleukin-1 β gene are associated with increased risk of non-small cell lung cancer. Int J Cancer. 109:353–356. 2004.
44	Hu HM, Tian Q, Baer M, et al: The C/EBP bZIP domain can mediate lipopolysaccharide induction of the proinflammatory cytokines interleukin-6 and monocyte chemoattractant protein-1. J Biol Chem. 275:16373–16381. 2000. View Article : Google Scholar
45	Yamaji H, Iizasa T, Koh E, et al: Correlation between interleukin 6 production and tumor proliferation in non-small cell lung cancer. Cancer Immunol Immunother. 53:786–792. 2004. View Article : Google Scholar : PubMed/NCBI
46	Xiao W, Hodge DR, Wang L, Yang X, Zhang X and Farrar WL: Co-operative functions between nuclear factors NFkappaB and CCAT/enhancer-binding protein-beta (C/EBP-beta) regulate the IL-6 promoter in autocrine human prostate cancer cells. Prostate. 61:354–370. 2004. View Article : Google Scholar
47	Tang T, Shi Y, Opalenik SR, et al: Expression of the TAL1/SCL transcription factor in physiological and pathological vascular processes. J Pathol. 210:121–129. 2006. View Article : Google Scholar : PubMed/NCBI
48	Erez A, Perelman M, Hewitt SM, et al: Sil overexpression in lung cancer characterizes tumors with increased mitotic activity. Oncogene. 23:5371–5377. 2004. View Article : Google Scholar : PubMed/NCBI
49	Glubb DM, Cerri E, Giese A, et al: Novel functional germline variants in the vascular endothelial growth factor receptor 2 gene (KDR) and their effect on gene expression and micro-vessel density in lung cancer. Clin Cancer Res. 17:5257–5267. 2011. View Article : Google Scholar
50	Sanmartin E, Jantus Lewintre E, Sirera R, et al: Soluble vascular endothelial growth factor receptor 2 (VEGFR2): New biomarker in advanced non-small cell lung cancer (NSCLC)? J Clin Oncol (Suppl). 27:e221082009.
51	Tanaka A, Itoh F, Nishiyama K, et al: Inhibition of endothelial cell activation by bHLH protein E2–2 and its impairment of angiogenesis. Blood. 115:4138–4147. 2010.
52	Tanaka A, Itoh F, Itoh S and Kato M: TAL1/SCL relieves the E2-2-mediated repression of VEGFR2 promoter activity. J Biochem. 145:129–135. 2009. View Article : Google Scholar : PubMed/NCBI