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High-density oligonucleotide microarrays and functional network analysis reveal extended lung carcinogenesis pathway maps and multiple interacting genes in NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] induced CD1 mouse lung tumor

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Abstract

Purpose

NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] is a nicotine-derived nitrosaminoketone contained in tobacco smoke used as a powerful chemical carcinogen for rodent experimental models of pulmonary carcinogenesis. To clarify its carcinogenetic mechanisms, we examined the expression status of 22,625 mouse genes.

Methods

The affymetrix GeneChip mouse expression 430 A arrays have been used in CD1-induced mouse lung tumor. The affected genes were analyzed by Ingenuity pathway analysis to investigate functional network and gene ontology.

Results

A total of 876 genes were found to be differentially expressed at least twofold between NNK-induced tumors and normal lung tissues, 390 up-regulated and 486 down-regulated in these lesions. The functions with the highest P values were related to cellular growth and proliferation (P = 1.71 × 10−4 to 4.10 × 10−2). In addition, we identified canonical pathways for Wnt/β-catenin signaling (P = 0.0338).

Conclusions

These results suggest that application of gene expression profiling may provide an improved strategy for therapeutic targeting of tobacco smoking-induced lung cancer.

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References

  • Belinsky SA, Devereux TR, Foley JF, Maronpot RR, Anderson MW (1992) Role of the alveolar type 2 cell in the development and progression of pulmonary tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in the A/J mouse. Cancer Res 52:3164–3173

    CAS  PubMed  Google Scholar 

  • Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98:13790–13795

    Article  CAS  PubMed  Google Scholar 

  • Borczuk AC ,Kim HK, Yegen HA, Friedman RA, Powell CA (2005) Lung adenocarcinoma global profiling identifies type II transforming growth factor-beta receptor as a repressor of invasiveness. Am J Respir Crit Care Med 172:729–737

    Article  PubMed  Google Scholar 

  • Castonguay A, Rioux N (1997) Inhibition of lung tumourigenesis by sulindac: comparison of two experimental protocols. Carcinogenesis 18(3):491–496

    Article  CAS  PubMed  Google Scholar 

  • Charalabopoulos K, Gogali A, Kostoula OK, Constantopoulos SH (2004) Cadherin superfamily of adhesion molecules in primary lung cancer. Exp Oncol 26:256–260

    CAS  PubMed  Google Scholar 

  • Dungworth DL, Rittinghausen S, Schwartz L, Harkema JR, Hayashi Y, Kittel B, Lewis D, Miller RA, Mohr U, Morgan KT, Rehm S, Slayter MV (2001) Respiratory system and mesothelium. In: Mohr U (ed) International classification of rodent tumors—the mouse. Springer, Berlin Heidelberg New York/WHO—International Agency for Research on Cancer, pp 87–137

  • Fukui T, Kondo M, Ito G, Maeda O, Sato N, Yoshioka H, Yokoi K, Ueda Y, Shimokata K, Sekido Y (2005) Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene 24:6323–6327

    Article  CAS  PubMed  Google Scholar 

  • Gebel S, Gerstmayer B, Bosio A, Haussmann HJ, Van Miert E, Müller T (2004) Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke. Carcinogenesis 25:169–178

    Article  CAS  PubMed  Google Scholar 

  • Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194–210

    Article  CAS  PubMed  Google Scholar 

  • Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11:559–603

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann D, Hoffmann I (1997) The changing cigarette, 1950–1995. J Toxicol Environ Health 50:307–364

    Article  CAS  PubMed  Google Scholar 

  • Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Ando H, Yanagisawa A, Tsuchiya E, Kato Y, Nakamura Y (1992) Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res 52:6696–6698

    CAS  PubMed  Google Scholar 

  • Izzotti A, Cartiglia C, Longobardi L, Bagnasco M, Merello A,You M, Lubet RA, De Flora S (2004) Gene expression in the lung of p53 mutant mice exposed to cigarette smoke. Cancer Res 64:8566–8572

    Article  CAS  PubMed  Google Scholar 

  • Katoh M (2003) Wnt 2 and gastrointestinal cancer. Int J Mol Med 12:811–816

    CAS  PubMed  Google Scholar 

  • Kohnoa H, Taimaa M, Sumidaa T, Azumac Y, Ogawad H, Tanakaa T (2001) Inhibitory effect of mandarin juice rich in β-cryptoxanthin and hesperidin on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanoneinduced pulmonary tumorigenesis in mice. Cancer Lett 174:141–150

    Article  Google Scholar 

  • Korinek V, Barker N, Morin PJ, Van Wichen D, De Weger R, Kinzler KW, Vogelstein B, Clevers H (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC −/− colon carcinoma. Science 275:1784–1787

    Article  CAS  PubMed  Google Scholar 

  • Lee CJ ,Appleby VJ, Orme AT, Chan WI, Scotting PJ (2002) Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 57:201–214

    Article  PubMed  Google Scholar 

  • Lockhart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, Mittmann M, Wang C, Kobayashi M, Horton H, Brown EL (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680

    Article  CAS  PubMed  Google Scholar 

  • Mazieres J, He B, You L, Xu Z, Jablons DM (2005) Wnt signaling in lung cancer. Cancer Lett 222:1–10

    Article  CAS  PubMed  Google Scholar 

  • McPherson JD, Marra M, Hillier L, Waterston RH, Chinwalla A, Wallis J, Sekhon M, Wylie K, Mardis ER, Wilson RK, Fulton R, Kucaba TA, Wagner-McPherson C, Barbazuk WB, Gregory SG, Humphray SJ, French L, Evans RS, Bethel G, Whittaker A, Holden JL, McCann OT, Dunham A, Soderlund C, Scott CE, Bentley DR, Schuler G, Chen HC, Jang W, Green ED, Idol JR, Maduro VV, Montgomery KT, Lee E, Miller A, Emerling S, Kucherlapati R, Gibbs R, Scherer S, Gorrell JH, Sodergren E, Clerc-Blankenburg K, Tabor P, Naylor S, Garcia D, de Jong PJ, Catanese JJ, Nowak N, Osoegawa K, Qin S, Rowen L, Madan A, Dors M, Hood L, Trask B, Friedman C, Massa H, Cheung VG, Kirsch IR, Reid T, Yonescu R, Weissenbach J, Bruls T, Heilig R, Branscomb E, Olsen A, Doggett N, Cheng JF, Hawkins T, Myers RM, Shang J, Ramirez L, Schmutz J, Velasquez O, Dixon K, Stone NE, Cox DR, Haussler D, Kent WJ, Furey T, Rogic S, Kennedy S, Jones S, Rosenthal A, Wen G, Schilhabel M, Gloeckner G, Nyakatura G, Siebert R, Schlegelberger B, Korenberg J, Chen XN, Fujiyama A, Hattori M, Toyoda A, Yada T, Park HS, Sakaki Y, Shimizu N, Asakawa S, Kawasaki K, Sasaki T, Shintani A, Shimizu A, Shibuya K, Kudoh J, Minoshima S, Ramser J, Seranski P, Hoff C, Poustka A, Reinhardt R, Lehrach H (2001) A physical map of the human genome. Nature (Lond.) 409:934–941

    Article  CAS  Google Scholar 

  • Minna JD, Roth JA, Gazdar AF (2002) Focus on lung cancer. Cancer Cell 1:49–52

    Article  CAS  PubMed  Google Scholar 

  • Morin JP, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Clevers H (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790

    Article  CAS  PubMed  Google Scholar 

  • Nettesheim P (1991) Cells of origin of primary neoplasm in mice. Exp Lung Res 17:215–217

    CAS  PubMed  Google Scholar 

  • Oreffo VI, Robinson S, You M, Wu MC, Malkinson AM (1998) Decreased expression of the adenomatous polyposis (APC) and mutated in colorectal cancer (Mcc) genes in mouse lung neoplasia. Mol Carcinogen 21:37–49

    Article  CAS  Google Scholar 

  • Rehm S, Word JM, Sass B (1994) Tumours of the lungs. In: Turusov VS, Mohrs U (eds) Pathology of tumours in laboratory animals, vol 2. Tumours of the Mouse, IARC, Lyon, pp 325–356

  • Salih HR, Kosowski SG, Haluska VF, Starling GC, Loo DT, Lee F, Aruffo AA, Trial PA, Kiener PA (2000) Constitutive expression of functional 4-1BB (CD137) ligand on carcinoma cells. J Immunol 165:2903–2910

    CAS  PubMed  Google Scholar 

  • Shigemitsu K, Sekido Y, Usami N, Mori S, Sato M, Horio Y, Hasegawa Y, Bader SA, Gazdar AF, Minna JD, Hida T, Yoshioka H, Imaizumi M, Ueda Y (2001) Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene 20:4249–4257

    Article  CAS  PubMed  Google Scholar 

  • Shimkin MB, Stoner GD (1975) Lung tumors in mice: application to carcinogenesis bioassay. Adv Cancer Res 21:1–58

    Article  CAS  PubMed  Google Scholar 

  • Stoner GD (1991) Lung tumors in strain A mice as a bioassay for carcinogenicity of environmental chemicals. Exp Lung Res 17:405–423

    CAS  PubMed  Google Scholar 

  • Sunaga N, Kohno T, Kolligs FT, Fearon ER, Saito R, Yokota J (2001) Constitutive activation of the Wnt signaling pathway by CTNNB1 (β-catenin) mutations in a subset of human lung adenocarcinoma. Genes Chromosomes Cancer 30:316–321

    Article  CAS  PubMed  Google Scholar 

  • Teicher BA (2001) Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev 20:133–143

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Fund of Smoking Research Foundation. We thank Mrs. Tokimasa Kumada and Hideki Hatta and Miss Kanako Yasuyoshi for their expert technical assistance.

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Authors and Affiliations

  1. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Hekmat Osman Abdel-Aziz, Kazuhiro Nomoto, Yoshihiro Murai, Koichi Tsuneyama & Yasuo Takano

  2. Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Ichiro Takasaki & Yoshiaki Tabuchi

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  1. Hekmat Osman Abdel-Aziz
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  2. Ichiro Takasaki
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  3. Yoshiaki Tabuchi
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  7. Yasuo Takano
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Correspondence to Yasuo Takano.

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Abdel-Aziz, H.O., Takasaki, I., Tabuchi, Y. et al. High-density oligonucleotide microarrays and functional network analysis reveal extended lung carcinogenesis pathway maps and multiple interacting genes in NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] induced CD1 mouse lung tumor. J Cancer Res Clin Oncol 133, 107–115 (2007). https://doi.org/10.1007/s00432-006-0149-x

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  • DOI: https://doi.org/10.1007/s00432-006-0149-x

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