Pathogenic mechanisms of lung adenocarcinoma in smokers and non-smokers determined by gene expression interrogation

Hu,Yunqian; Chen,Guohan

doi:10.3892/ol.2015.3462

Pathogenic mechanisms of lung adenocarcinoma in smokers and non-smokers determined by gene expression interrogation

Authors:
- Yunqian Hu
- Guohan Chen
View Affiliations

Affiliations: Department of Respiration, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, Department of Thoracic Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
Published online on: July 7, 2015 https://doi.org/10.3892/ol.2015.3462
Pages: 1350-1370
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cigarette smoking is the leading risk factor for lung cancer, which accounts for the highest number of cancer‑related mortalities worldwide in men and women. Individuals with a history of smoking are 15‑30 times more likely to develop lung cancer compared with those who do not smoke. However, our understanding of the underlying molecular mechanisms that contribute to lung tumorigenesis in smokers versus non‑smokers remains incomplete. In order to investigate such mechanisms, the present study aimed to systemically interrogate microarray datasets from tumor biopsies and matching normal tissues from stage I and II lung adenocarcinoma patients who had never smoked or were current smokers. The gene expression analysis identified 422 (99 upregulated and 323 downregulated) and 534 (174 upregulated and 360 downregulated) differentially‑expressed genes from the never‑smokers and current smokers, respectively, and the two groups shared 277 genes that exhibited similar trends of alteration. These genes encode regulators that are involved in a variety of cellular functions, including collagen metabolism and homeostasis of caveolae plasma membranes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes characterization indicated that biological pathways, including extracellular matrix‑receptor interaction and cell migration and proliferation, were all affected in the lung cancer patients regardless of the smoking status. However, smoking induced a unique gene expression pattern characterized by upregulation of cell cycle regulators (CDK1, CCNB1 and CDC20), as well as significantly affected biological networks, including p53 signaling pathways. Taken together, these findings suggest novel mechanistic insights, and provide an improved understanding of the smoking‑induced molecular alterations that contribute to the pathogenesis of lung adenocarcinoma.

View Figures

View References

1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2	Surveillance, Epidemiology, and End Results Program, . SEER Stat Fact Sheets. Lung and Bronchus Cancer. National Cancer Institute at the National Institutes of Health. http://seer.cancer.gov/statfacts/html/lungb.htmlAccessed. March 24–2015.
3	Peto R, Darby S, Deo H, Silcocks P, Whitley E and Doll R: Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case-control studies. BMJ. 321:323–329. 2000. View Article : Google Scholar : PubMed/NCBI
4	Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, et al: Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 40:616–622. 2008. View Article : Google Scholar : PubMed/NCBI
5	Cornfield J, Haenszel W, Hammond EC, et al: Smoking and lung cancer: Recent evidence and a discussion of some questions. 1959. Int J Epidemiol. 38:1175–1191. 2009. View Article : Google Scholar
6	Shigematsu H, Takahashi T, Nomura M, Majmudar K, Suzuki M, Lee H, Wistuba II, Fong KM, Toyooka S, Shimizu N, et al: Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 65:1642–1646. 2005. View Article : Google Scholar : PubMed/NCBI
7	Hecht SS: Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 91:1194–1210. 1999. View Article : Google Scholar : PubMed/NCBI
8	Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, et al: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 150:1107–1120. 2012. View Article : Google Scholar : PubMed/NCBI
9	Govindan R, Ding L, Griffith M, et al: Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 150:1121–1134. 2012. View Article : Google Scholar : PubMed/NCBI
10	Le Calvez F, Mukeria A, Hunt JD, Kelm O, Hung RJ, Tanière P, Brennan P, Boffetta P, Zaridze DG and Hainaut P: TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res. 65:5076–5083. 2005. View Article : Google Scholar : PubMed/NCBI
11	Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, et al: EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 101:13306–13311. 2004. View Article : Google Scholar : PubMed/NCBI
12	Landi MT, Dracheva T, Rotunno M, et al: Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS One. 3:e16512008. View Article : Google Scholar : PubMed/NCBI
13	Wu J, Irizarry R, MacDonald J and Gentry J: RIwcf JMJ. gcrma. Background Adjustment Using Sequence Information. R package version 2.38.0.
14	Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. January 20–2015.(Epub ahead of print). doi: 10.1093/nar/gkv007. View Article : Google Scholar
15	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2013. View Article : Google Scholar
16	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
17	Warnes GR, Bolker B, Bonebakker L, Gentleman R, Liaw WHA, Lumley T, Maechler M, Magnusson A, Moeller S, Schwartz M and Venables B: gplots: Various R Programming Tools for Plotting Data. R package version 2.16.0.
18	Carlson M: GO.db: A set of annotation maps describing the entire Gene Ontology. R package version 3.0.0.
19	Carlson M: KEGG.db: A set of annotation maps for KEGG. R package version 3.0.0.
20	Tenenbaum D: KEGGREST: Client-side REST access to KEGG. R package version 1.6.4.
21	Mo YQ, Dai L, Zheng DH, Zhu LJ, Wei XN, Pessler F, Shen J and Zhang BY: Synovial infiltration with CD79a-positive B cells, but not other B cell lineage markers, correlates with joint destruction in rheumatoid arthritis. J Rheumatol. 38:2301–2308. 2011. View Article : Google Scholar : PubMed/NCBI
22	Han F, Gu D, Chen Q and Zhu H: Caveolin-1 acts as a tumor suppressor by down-regulating epidermal growth factor receptor-mitogen-activated protein kinase signaling pathway in pancreatic carcinoma cell lines. Pancreas. 38:766–774. 2009. View Article : Google Scholar : PubMed/NCBI
23	Lobos-González L, Aguilar L, Diaz J, et al: E-cadherin determines Caveolin-1 tumor suppression or metastasis enhancing function in melanoma cells. Pigment Cell Melanoma Res. 26:555–570. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: The Gene Ontology Consortium: Gene ontology: Tool for the unification of biology. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
25	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
26	Rudin CM, Avila-Tang E, Harris CC, Herman JG, Hirsch FR, Pao W, Schwartz AG, Vahakangas KH and Samet JM: Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res. 15:5646–5661. 2009. View Article : Google Scholar : PubMed/NCBI
27	Szymanowska-Narloch A, Jassem E, Skrzypski M, Muley T, Meister M, Dienemann H, Taron M, Rosell R, Rzepko R, Jarząb M, et al: Molecular profiles of non-small cell lung cancers in cigarette smoking and never-smoking patients. Adv Med Sci. 58:196–206. 2013. View Article : Google Scholar : PubMed/NCBI
28	Woenckhaus M, Klein-Hitpass L, Grepmeier U, Merk J, Pfeifer M, Wild P, Bettstetter M, Wuensch P, Blaszyk H, Hartmann A, et al: Smoking and cancer-related gene expression in bronchial epithelium and non-small-cell lung cancers. J Pathol. 210:192–204. 2006. View Article : Google Scholar : PubMed/NCBI
29	Spira A, Beane JE, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas YM, Calner P, Sebastiani P, et al: Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 13:361–366. 2007. View Article : Google Scholar : PubMed/NCBI
30	Staaf J, Jönsson G, Jönsson M, Karlsson A, Isaksson S, Salomonsson A, Pettersson HM, Soller M, Ewers SB, Johansson L, et al: Relation between smoking history and gene expression profiles in lung adenocarcinomas. BMC Med Genomics. 5:222012. View Article : Google Scholar : PubMed/NCBI
31	Du X, Qian X, Papageorge A, Schetter AJ, Vass WC, Liu X, Braverman R, Robles AI and Lowy DR: Functional interaction of tumor suppressor DLC1 and caveolin-1 in cancer cells. Cancer Res. 72:4405–4416. 2012. View Article : Google Scholar : PubMed/NCBI
32	Chanvorachote P and Chunhacha P: Caveolin-1 regulates endothelial adhesion of lung cancer cells via reactive oxygen species-dependent mechanism. PLoS One. 8:e574662013. View Article : Google Scholar : PubMed/NCBI
33	Wang Z, Sokolovska A, Seymour R, Sundberg JP and Hogenesch H: SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells. PLoS One. 7:e318092012. View Article : Google Scholar : PubMed/NCBI
34	Pancotti F, Roncuzzi L, Maggiolini M and Gasperi-Campani A: Caveolin-1 silencing arrests the proliferation of metastatic lung cancer cells through the inhibition of STAT3 signaling. Cell Signal. 24:1390–1397. 2012. View Article : Google Scholar : PubMed/NCBI
35	Luanpitpong S, Talbott SJ, Rojanasakul Y, Nimmannit U, Pongrakhananon V, Wang L and Chanvorachote P: Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. J Biol Chem. 285:38832–38840. 2010. View Article : Google Scholar : PubMed/NCBI
36	Wang Z, Potter CS, Sundberg JP and Hogenesch H: SHARPIN is a key regulator of immune and inflammatory responses. J Cell Mol Med. 16:2271–2279. 2012. View Article : Google Scholar : PubMed/NCBI
37	Lemjabbar H, Li D, Gallup M, Sidhu S, Drori E and Basbaum C: Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem. 278:26202–26207. 2003. View Article : Google Scholar : PubMed/NCBI
38	Luppi F, Aarbiou J, van Wetering S, et al: Effects of cigarette smoke condensate on proliferation and wound closure of bronchial epithelial cells in vitro: Role of glutathione. Respir Res. 6:1402005. View Article : Google Scholar : PubMed/NCBI
39	Schaal C and Chellappan SP: Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers. Mol Cancer Res. 12:14–23. 2014. View Article : Google Scholar : PubMed/NCBI
40	Liu C, Russell RM and Wang XD: Lycopene supplementation prevents smoke-induced changes in p53, p53 phosphorylation, cell proliferation, and apoptosis in the gastric mucosa of ferrets. J Nutr. 136:106–111. 2006.PubMed/NCBI
41	Dasgupta P, Rastogi S, Pillai S, et al: Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest. 116:2208–2217. 2006. View Article : Google Scholar : PubMed/NCBI
42	Potter CS, Wang Z, Silva KA, et al: Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. PLoS One. 9:e856662014. View Article : Google Scholar : PubMed/NCBI
43	Conklin BS, Zhao W, Zhong DS and Chen C: Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am J Pathol. 160:413–418. 2002. View Article : Google Scholar : PubMed/NCBI
44	Jull BA, Plummer HK III and Schuller HM: Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway, resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells. J Cancer Res Clin Oncol. 127:707–717. 2001.PubMed/NCBI
45	Furrukh M: Tobacco Smoking and Lung Cancer: Perception-changing facts. Sultan Qaboos Univ Med J. 13:345–358. 2013. View Article : Google Scholar : PubMed/NCBI
46	Pfeifer GP, Denissenko MF, Olivier M, et al: Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 21:7435–7451. 2002. View Article : Google Scholar : PubMed/NCBI
47	Husgafvel-Pursiainen K and Kannio A: Cigarette smoking and p53 mutations in lung cancer and bladder cancer. Environ Health Perspect. 104 (Suppl 3):553–556. 1996. View Article : Google Scholar : PubMed/NCBI
48	Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, Couch MJ, Forastiere AA and Sidransky D: Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med. 332:712–717. 1995. View Article : Google Scholar : PubMed/NCBI
49	Muller PA and Vousden KH: p53 mutations in cancer. Nat Cell Biol. 15:2–8. 2013. View Article : Google Scholar : PubMed/NCBI
50	Muller PA and Vousden KH: Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 25:304–317. 2014. View Article : Google Scholar : PubMed/NCBI