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Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature

Oncogene volume 31, pages 4550–4558 (2012)Cite this article

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Abstract

Chronic inflammation is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC). The causes of inflammation in ESCC, however, are undefined. Dietary zinc (Zn)-deficiency (ZD) increases the risk of ESCC. We have previously shown that short-term ZD (6 weeks) in rats induces overexpression of the proinflammatory mediators S100a8 and S100a9 in the esophageal mucosa with accompanying esophageal epithelial hyperplasia. Here we report that prolonged ZD (21 weeks) in rats amplified this inflammation that when combined with non-carcinogenic low doses of the environmental carcinogen, N-nitrosomethylbenzylamine (NMBA) elicited a 66.7% (16/24) incidence of ESCC. With Zn-sufficiency, NMBA produced no cancers (0/21) (P<0.001). At tumor endpoint, the neoplastic ZD esophagus, as compared with Zn-sufficient esophagus, had an inflammatory gene signature with upregulation of numerous cancer-related inflammation genes (CXC and CC chemokines, chemokine receptors, cytokines and Cox-2) in addition to S100a8 and S100a9. This signature was already activated in the earlier dysplastic stage. Additionally, time-course bioinformatics analysis of expression profiles at tumor endpoint and before NMBA exposure revealed that this sustained inflammation was due to ZD rather than carcinogen exposure. Importantly, Zn replenishment reversed this inflammatory signature at both the dysplastic and neoplastic stages of ESCC development, and prevented cancer formation. Thus, the molecular definition of ZD-induced inflammation as a critical factor in ESCC development has important clinical implications with regard to development and prevention of this deadly disease.

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References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917.

    Article  CAS  Google Scholar 

  2. Balkwill F, Mantovani A . Inflammation and cancer: back to Virchow? Lancet 2001; 357: 539–545.

    Article  CAS  Google Scholar 

  3. Coussens LM, Werb Z . Inflammation and cancer. Nature 2002; 420: 860–867.

    Article  CAS  Google Scholar 

  4. Karin M . Nuclear factor-kappaB in cancer development and progression. Nature 2006; 441: 431–436.

    Article  CAS  Google Scholar 

  5. Mandard AM, Hainaut P, Hollstein M . Genetic steps in the development of squamous cell carcinoma of the esophagus. Mutat Res 2000; 462: 335–342.

    Article  CAS  Google Scholar 

  6. Magee PN . The experimental basis for the role of nitroso compounds in human cancer. Cancer Surv 1989; 8: 207–239.

    CAS  PubMed  Google Scholar 

  7. Yang CS . Research on esophageal cancer in China: a review. Cancer Res 1980; 40 (8 Part 1): 2633–2644.

    CAS  PubMed  Google Scholar 

  8. Abnet CC, Lai B, Qiao YL, Vogt S, Luo XM, Taylor PR et al. Zinc concentration in esophageal biopsy specimens measured by x-ray fluorescence and esophageal cancer risk. J Natl Cancer Inst 2005; 97: 301–306.

    Article  CAS  Google Scholar 

  9. Kmet J, Mahboubi E . Esophageal cancer in the Caspian littoral of Iran: initial studies. Science 1972; 175: 846–853.

    Article  CAS  Google Scholar 

  10. Poschl G, Seitz HK . Alcohol and cancer. Alcohol Alcohol 2004; 39: 155–165.

    Article  CAS  Google Scholar 

  11. Ho E, Ames BN . Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci USA 2002; 99: 16770–16775.

    Article  CAS  Google Scholar 

  12. Prasad AS, Kucuk O . Zinc in cancer prevention. Cancer Metastasis Rev 2002; 21: 291–295.

    Article  CAS  Google Scholar 

  13. Vallee BL, Falchuk KH . The biochemical basis of zinc physiology. Physiol Rev 1993; 73: 79–118.

    Article  CAS  Google Scholar 

  14. Rink L, Haase H . Zinc homeostasis and immunity. Trends Immunol 2007; 28: 1–4.

    Article  CAS  Google Scholar 

  15. Berg JM, Shi Y . The galvanization of biology: a growing appreciation for the roles of zinc. Science 1996; 271: 1081–1085.

    Article  CAS  Google Scholar 

  16. Stinson SF, Squire RA, Sporn MB . Pathology of esophageal neoplasms and associated proliferative lesions induced in rats by N-methyl-N-benzylnitrosamine. J Natl Cancer Inst 1978; 61: 1471–1475.

    CAS  PubMed  Google Scholar 

  17. Stoner GD, Gupta A . Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis 2001; 22: 1737–1746.

    Article  CAS  Google Scholar 

  18. Pegg AE . Methylation of the O6 position of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents. Cancer Invest 1984; 2: 223–231.

    Article  CAS  Google Scholar 

  19. Lozano JC, Nakazawa H, Cros MP, Cabral R, Yamasaki H . G--&gt;A mutations in p53 and Ha-ras genes in esophageal papillomas induced by N-nitrosomethylbenzylamine in two strains of rats. Mol Carcinog 1994; 9: 33–39.

    Article  CAS  Google Scholar 

  20. Fong LY, Nguyen VT, Farber JL . Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst 2001; 93: 1525–1533.

    Article  CAS  Google Scholar 

  21. Fong LY, Zhang L, Jiang Y, Farber JL . Dietary zinc modulation of COX-2 expression and lingual and esophageal carcinogenesis in rats. J Natl Cancer Inst 2005; 97: 40–50.

    Article  CAS  Google Scholar 

  22. Taccioli C, Wan SG, Liu CG, Alder H, Volinia S, Farber JL et al. Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophageal preneoplasia in the rat. Gastroenterology 2009; 136: 953–966.

    Article  CAS  Google Scholar 

  23. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    Article  CAS  Google Scholar 

  24. Gebhardt C, Nemeth J, Angel P, Hess J . S100A8 and S100A9 in inflammation and cancer. Biochem Pharmacol 2006; 72: 1622–1631.

    Article  CAS  Google Scholar 

  25. Balkwill F . Cancer and the chemokine network. Nat Rev Cancer 2004; 4: 540–550.

    Article  CAS  Google Scholar 

  26. Williams CS, Mann M, DuBois RN . The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999; 18: 7908–7916.

    Article  CAS  Google Scholar 

  27. Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 2003; 100: 2645–2650.

    Article  CAS  Google Scholar 

  28. Karin M, Greten FR . NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005; 5: 749–759.

    Article  CAS  Google Scholar 

  29. Eltzschig HK, Carmeliet P . Hypoxia and inflammation. N Engl J Med 2011; 364: 656–665.

    Article  CAS  Google Scholar 

  30. Cintorino M, Tripod SA, Santopietro R, Antonio P, Lutfi A, Chang F et al. Cytokeratin expression patterns as an indicator of tumour progression in oesophageal squamous cell carcinoma. Anticancer Res 2001; 21: 4195–4201.

    CAS  PubMed  Google Scholar 

  31. Huang da W, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44–57.

    Article  Google Scholar 

  32. Roussos ET, Condeelis JS, Patsialou A . Chemotaxis in cancer. Nat Rev Cancer 2011; 11: 573–587.

    Article  CAS  Google Scholar 

  33. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410: 471–475.

    Article  CAS  Google Scholar 

  34. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 2008; 14: 408–419.

    Article  CAS  Google Scholar 

  35. Wang B, Hendricks DT, Wamunyokoli F, Parker MI . A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. Cancer Res 2006; 66: 3071–3077.

    Article  CAS  Google Scholar 

  36. Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K . Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999; 59: 198–204.

    CAS  Google Scholar 

  37. Kaifi JT, Yekebas EF, Schurr P, Obonyo D, Wachowiak R, Busch P et al. Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer. J Natl Cancer Inst 2005; 97: 1840–1847.

    Article  CAS  Google Scholar 

  38. Kumar A, Chatopadhyay T, Raziuddin M, Ralhan R . Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. Int J Cancer 2007; 120: 230–242.

    Article  CAS  Google Scholar 

  39. Allavena P, Germano G, Marchesi F, Mantovani A . Chemokines in cancer related inflammation. Exp Cell Res 2011; 317: 664–673.

    Article  CAS  Google Scholar 

  40. Miyazaki H, Patel V, Wang H, Edmunds RK, Gutkind JS, Yeudall WA . Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res 2006; 66: 4279–4284.

    Article  CAS  Google Scholar 

  41. Richmond A . Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol 2002; 2: 664–674.

    Article  CAS  Google Scholar 

  42. Yamamoto K, Kitayama W, Denda A, Morisaki A, Kuniyasu H, Inoue M et al. Suppressive effects of a selective cyclooxygenase-2 inhibitor, etodolac, on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Exp Toxicol Pathol 2004; 56: 145–151.

    Article  CAS  Google Scholar 

  43. Nemeth J, Stein I, Haag D, Riehl A, Longerich T, Horwitz E et al. S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis. Hepatology 2009; 50: 1251–1262.

    Article  CAS  Google Scholar 

  44. Hiscott J, Marois J, Garoufalis J, D’Addario M, Roulston A, Kwan I 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 1993; 13: 6231–6240.

    Article  CAS  Google Scholar 

  45. Sun J, Liu J, Pan X, Quimby D, Zanesi N, Druck T et al. Effect of zinc supplementation on N-nitrosomethylbenzylamine-induced forestomach tumor development and progression in tumor suppressor-deficient mouse strains. Carcinogenesis 2011; 32: 351–358.

    Article  CAS  Google Scholar 

  46. Fong LY, Jiang Y, Rawahneh ML, Smalley KJ, Croce CM, Farber JL et al. Zinc supplementation suppresses 4-nitroquinoline 1-oxide-induced rat oral carcinogenesis. Carcinogenesis 2011; 32: 554–560.

    Article  CAS  Google Scholar 

  47. Bolstad BM, Irizarry RA, Astrand M, Speed TP . A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003; 19: 185–193.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Kay Huebner (The Ohio State University) for reading and critical discussion of the manuscript. We thank Shao-gui Wan's assistance with animal care and validation of the array data. The microarray data were submitted to ArrayExpress (Accession number: E-MTAB-428). This work was supported by NIH grants R01CA118560 (LYYF) and R01CA115965 (CMC).

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Author notes

  1. C Taccioli

    Present address: 7Current address: Department of Cancer Biology, Paul O’Gorman Cancer Institute, University College London, London WC1E 6B, UK,

  2. C Taccioli and H Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    C Taccioli, X P Liu & C M Croce

  2. Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA

    H Chen, Y Jiang & L Y Fong

  3. Biomedical Informatics, Ohio State University, Columbus, OH, USA

    K Huang

  4. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    K J Smalley & L Y Fong

  5. Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA

    J L Farber

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  1. C Taccioli
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Correspondence to L Y Fong.

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Taccioli, C., Chen, H., Jiang, Y. et al. Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature. Oncogene 31, 4550–4558 (2012). https://doi.org/10.1038/onc.2011.592

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