Medical Oncology

, Volume 28, Issue 1, pp 377–384 | Cite as

Nitrative and oxidative DNA damage as potential survival biomarkers for nasopharyngeal carcinoma

  • Yuan-Jiao Huang
  • Bei-Bei Zhang
  • Ning Ma
  • Mariko Murata
  • An-zhou Tang
  • Guang-Wu Huang
Original Paper

Abstract

Currently, there are no satisfactory biomarkers available to screen for nasopharyngeal carcinoma (NPC). Nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), has been suggested to cause nitrative and oxidative stress, leading to the accumulation of 8-nitroguanine (8-NitroG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) and the subsequent transversion mutation of DNA. The aim of this study was to evaluate iNOS expression and the status of nitrative and oxidative stress in NPC. Fifty-nine cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of iNOS and the formation of 8-NitroG and 8-OHdG, using double-immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using the Mann–Whitney test. Thirty-six patients from the 57 cases of NPC and 36 healthy controls were investigated to examine the level of serum 8-OHdG, using enzyme-linked immunosorbent assay (ELISA). The statistical differences were analyzed using a t test. Strong DNA lesions were observed in the cancer cells of NPC patients. All cases of NPC were positive for 8-NitroG and 8-OHdG, and 54 (94.7%) were positive for iNOS. NPC samples exhibited significantly more intense staining for 8-NitroG, 8-OHdG and iNOS than those of chronic nasopharyngitis (P < 0.05, respectively). The mean value of serum 8-OHdG in the 36 NPC patients was 0.538 ± 0.336 ng/ml compared to 0.069 ± 0.059 ng/ml for the healthy controls. The difference in the serum levels of 8-OHdG between the NPC patients and controls was statistically significant (P < 0.05). Our present findings suggest that pathological stimulation of nasopharyngeal tissue, caused by bacterial, viral or parasitic inflammation, may lead to nitrative and oxidative DNA lesions, caused by NO. This may contribute to the cause and development of NPC. Thus, 8-NitroG and 8-OHdG could be potential biomarkers for evaluating the risk of NPC. Better understanding of the molecular mechanisms underlying nitrative and oxidative DNA damage may provide clues to molecular targets for new approaches of NPC prevention.

Keywords

Nasopharyngeal carcinoma 8-nitroguanine 8-hydroxy-2′-deoxyguanosine Nitrative DNA damage Oxidative DNA damage 

Notes

Acknowledgments

Project supported by Local High Disease Control and Prevention Research Laboratory Foundation of Guangxi, China (NO.0630006-5E7Z; NO.0842009-Z14); The Natural Science Foundation of Guangxi, China (No.06390-18).

Competing interests

The authors declare that they have no competing interests.

References

  1. 1.
    Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005;365(9476):2041–54.PubMedCrossRefGoogle Scholar
  2. 2.
    Ho J. Nasopharyngeal carcinoma (NPC). Adv Cancer Res. 1972;15:57–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Jeannel D, Bouvier G, Huber A. Nasopharyngeal carcinoma: an epidemiological approach to carcinogenesis. Cancer Surv. 1999;33:125–55.Google Scholar
  4. 4.
    Mcdermott AL, Dutt SN, Watkinson JC. The aetiology of naopharyngeal carcinoma. Clin Otolaryngol Allied Sci. 2001;26:82–92.PubMedCrossRefGoogle Scholar
  5. 5.
    Working Group IARC. Epstein-Barr virus IARC monographs on the evaluation of carcinogenic risks to humans, vol. 70. Lyon: IARC Press; 1997. p. 47–373.Google Scholar
  6. 6.
    Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell. 2004;5:423–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Yu MC, Garabrant DH, Huang TB, et al. Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J Cancer. 1990;45:1033–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Armstrong RW, Imrey PB, Lye MS, Armstrong MJ, Yu MC, Sani S. Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat. Int J Epidemiol. 2000;29:991–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Hildesheim A, Dosemeci M, Chan CC, et al. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2001;10:1145–53.PubMedGoogle Scholar
  10. 10.
    Coussens M, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3:276–85.PubMedCrossRefGoogle Scholar
  12. 12.
    Ohshima H, Tatemichi M, Sawa T. Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys. 2003;417:3–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Akaike T, Maeda H. Nitric oxide and virus infection. Immunology. 2000;101:300–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Nair J, Gansauge F, Beger H, et al. Increased etheno DNA adducts in affected tissues of patients suffering from Crohn’s disease, ulcerative colitis, and chronic pancreatitis. Antioxid Redox Signal. 2006;8:1003–10.PubMedCrossRefGoogle Scholar
  15. 15.
    Majano PL, Garcia-Monzon C, Lopez-Cabrera M, et al. Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. J Clin Invest. 1998;101:1343–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Schweyer S, Mihm S, Radzun HJ, Hartmann H, et al. Liver infiltrating T lymphocytes express interferon gamma and inducible nitric oxide synthase in chronic hepatitis C virus infection. Gut. 2000;46:255–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Brunet LR, Beall M, Dunne DW, et al. Nitric oxide and the Th2 response combine to prevent severe hepatic damage during Schistosoma mansoni infection. J Immunol. 1999;163:4976–84.PubMedGoogle Scholar
  18. 18.
    Ohshima H, Bandaletova TY, Brouet I, et al. Increased nitrosamine and nitrate biosynthesis mediated by nitric oxide synthase induced in hamsters infected with liver fluke (Opisthorchis viverrini). Carcinogenesis. 1994;15:271–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Tatemichi M, Ogura T, Nagata H, et al. Enhanced expression of inducible nitric oxide synthase in chronic gastritis with intestinal metaplasia. J Clin Gastroenterol. 1998;27:240–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Wheeler MA, Smith SD, Garcia-Cardena G, et al. Bacterial infection induces nitric oxide synthase in human neutrophils. J Clin Invest. 1997;99:110–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Tanaka S, Choe N, Hemenway DR, et al. Asbestos inhalation induces reactive nitrogene species and nitrotyrosine formation in the lungs and pleura of the rat. J Clin Invest. 1998;102:445–54.PubMedCrossRefGoogle Scholar
  22. 22.
    Yermilov V, Rubio J, Ohshima H. Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination. FEBS Lett. 1995;376:207–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Kawanishi S, Hiraku Y. Oxidative and nitrative DNA damage as biomarker for carcinogenesis with special reference to inflammation. Antioxid Redox Signal. 2006;8:1047–58.PubMedCrossRefGoogle Scholar
  24. 24.
    Dizdaroglu M. Oxidative damage to DNA in mammalian chromatin. Mutat Res. 1992;275:331–42.PubMedGoogle Scholar
  25. 25.
    Grollman AP, Moriya M. Mutagenesis by 8-oxoguanine: an enemy within. Trends Genet. 1993;9:246–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Tsuruya K, Furuichi M, Tominaga Y, et al. Accumulation of 8-oxoguanine in the cellular DNA and the alteration of the OGG1 expression during ischemiareperfusion injury in the rat kidney. DNA Repair (Amst). 2003;2:211–29.CrossRefGoogle Scholar
  27. 27.
    Tschugguel W, Schneeberger C, Unfried G, et al. Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. Breast Cancer Res Treat. 1999;56:145–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Tanaka H, Kijima H, Tokunaga T, et al. Frequent expression of inducible nitric oxide synthase in esophageal squamous cell carcinomas. Int J Oncol. 1999;14:1069–73.PubMedGoogle Scholar
  29. 29.
    Liu CY, Wang CH, Chen TC, et al. Increased level exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer. 1998;78:534–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Ambs S, Merriam WG, Bennett WP, et al. Frequent nitric oxide synthase-2 expression in human colon adenomas: implication for tumor angiogenesis and colon cancer progression. Cancer Res. 1998;58:334–41.PubMedGoogle Scholar
  31. 31.
    Klotz T, Bloch W, Volberg C, et al. Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer. 1998;82:1897–903.PubMedCrossRefGoogle Scholar
  32. 32.
    Gallo O, Masini E, Morbidelli L, et al. Role of nitric oxide in angiogenesis and tumor progression in head and neck cancer. J Natl Cancer Inst. 1998;90:587–96.PubMedCrossRefGoogle Scholar
  33. 33.
    Tatemichi M, Tazawa H, Masuda M, et al. Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in Trp53-deficient mice lacking inducible nitric oxide synthase gene. Int J Cancer. 2004;111:819–28.PubMedCrossRefGoogle Scholar
  34. 34.
    Szabo C, Ohahima H. DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide. 1997;1:373–85.PubMedCrossRefGoogle Scholar
  35. 35.
    Burney S, Caulfield JL, Niles JC, et al. The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res. 1999;424:37–49.PubMedGoogle Scholar
  36. 36.
    Dedon PC, Tannenbaum SR. Reactive nitrogen species in the chemical biology of inflammation. Arch Biochem Biophys. 2004;423:12–22.PubMedCrossRefGoogle Scholar
  37. 37.
    Puhakka AR, Harju TH, Paakko PK, et al. Nitric oxide synthases are associated with bronchial dysplasia. Lung Cancer. 2006;51:275–82.PubMedCrossRefGoogle Scholar
  38. 38.
    Anazawa T, Dimayuga PC, Li H, et al. Effect of exposure to cigarette smoke on carotid artery intimal thickening: the role of inducible NO synthase. Arterioscler Thromb Vasc Biol. 2004;24:1652–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Zaki MH, Akuta T, Akaike T. Nitric oxide-induced nitrative stress involved in microbial pathogenesis. J Pharmacol Sci. 2005;98:117–29.PubMedCrossRefGoogle Scholar
  40. 40.
    Ishima Y, Sawa T, Kragh-Hansen U, et al. S-Nitrospylation of human variant albumin Liprizzi (R410C) confers potent antibacterial and cytoprotective properties. J Pharmacol Exp Ther. 2007;320:969–77.PubMedCrossRefGoogle Scholar
  41. 41.
    Yermilov V, Rubio J, Becchi M, et al. Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis. 1995;16:2045–50.PubMedCrossRefGoogle Scholar
  42. 42.
    Loeb LA, Preston BD. Mutagenesis by apurinic/apyrimidinic sites. Annu Rev Genet. 1986;20:201–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Suzuki N, Yasui M, Geacintov NE, et al. Miscoding events during DNA synthesis past the nitration-damaged base 8-nitroguanine. Biochemistry. 2005;44:9238–45.PubMedCrossRefGoogle Scholar
  44. 44.
    Wu X, Takenaka K, Sonoda E, et al. Critical roles for polymerase ζ in cellular tolerance to nitric oxide-induced DNA damage. Cancer Res. 2006;66:748–54.PubMedCrossRefGoogle Scholar
  45. 45.
    Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Bruner SD, Norman DP, Verdine GL. Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature. 2000;403:859–66.PubMedCrossRefGoogle Scholar
  47. 47.
    Shang ZJ, Li ZB, Li JR. In vitro effects of nitric oxide synthase inhibitor L-NAME on oral squamous cell carcinoma: a preliminary study. Int J Oral Maxillofac Surg. 2006;35:539–54.PubMedCrossRefGoogle Scholar
  48. 48.
    Ponti D, Zaffaroni N, Capelli C, et al. Breast cancer stem cells: an overview. Eur J Cancer. 2006;42:1219–24.PubMedCrossRefGoogle Scholar
  49. 49.
    Alison MR, Lovell MJ. Liver cancer: the role of stem cells. Cell Prolif. 2005;38:407–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Yuan-Jiao Huang
    • 1
  • Bei-Bei Zhang
    • 1
  • Ning Ma
    • 2
  • Mariko Murata
    • 3
  • An-zhou Tang
    • 4
  • Guang-Wu Huang
    • 4
  1. 1.Medical Scientific Research CenterGuangxi Medical UniversityNanningPeople’s Republic of China
  2. 2.Suzuka University of Medical ScienceSuzukaJapan
  3. 3.Department of Environmental and Molecular MedicineMie University Graduate School of MedicineMieJapan
  4. 4.The First Affiliated HospitalGuangxi Medical UniversityNanningPeople’s Republic of China

Personalised recommendations