Advertisement

Tumor Biology

, Volume 34, Issue 6, pp 3923–3931 | Cite as

Nicotinamide N-methyltransferase overexpression is associated with Akt phosphorylation and indicates worse prognosis in patients with nasopharyngeal carcinoma

  • Khin Than Win
  • Sung-Wei Lee
  • Hsuan-Ying Huang
  • Li-Ching Lin
  • Ching-Yih Lin
  • Chung-Hsi Hsing
  • Li-Tzong Chen
  • Chien-Feng Li
Research Article

Abstract

Nicotinamide N-methyltransferase (NNMT) is overexpressed in many human cancers and is associated with poor prognosis. Akt (also known as protein kinase B) is an evolutionarily conserved serine/threonine kinase, serving as a downstream effector of the phosphatidylinositol 3-kinase signaling pathway. NNMT was first identified as a differentially upregulated gene in nasopharyngeal cancer tissues through data mining from published transcriptomic databases. Since no prior study has attempted to evaluate the clinical significance of NNMT or phosphorylated Akt (pAkt) expression in nasopharyngeal cancer, this study explores their expression in a large cohort of patients with nasopharyngeal cancer. The study included 124 nasopharyngeal cancer patients who were free of distant metastasis at initial diagnosis. Pathological slides were reviewed and clinical findings collected. We evaluated the expression of NNMT and pAkt immunohistochemically, stratified them into two groups (high and low expression) and examined the correlation with disease-specific survival (DSS), metastasis-free survival (MeFS), local recurrence-free survival (LRFS), and various clinicopathological factors. NNMT expression was significantly positively associated with pAkt expression. The high expression of both markers was significantly associated with an increment of tumor stage (p = 0.006 and p = 0.006, respectively). High expression of NNMT correlated significantly with a more aggressive clinical course and a significantly shorter DSS. Furthermore, NNMT expression and pAkt expression were strongly predictive of MeFS (p = 0.008; p = 0.0063) and LRFS (p = 0.005; p = 0.0125). In multivariate analysis, high expression of NNMT remained as a robust prognosticator for both end points evaluated. It independently portended inferior DSS (p = 0.02, HR = 1.976) and worse MeFS (p = 0.029, HR = 2.022) after tumor stage (p = 0.033, HR = 2.150; p = 0.028, HR = 2.942, for DSS and LRFS, respectively). We found NNMT positively correlated with pAkt expression and was independent adverse prognosticators of patient survival. NNMT therefore has potential utility as an indicator for prognosis, predicting treatment response to chemotherapy or radiation therapy, and even as a therapeutic target in the future.

Keywords

Nasopharyngeal carcinoma NNMT pAkt Prognosis 

Abbreviations

NNMT

Nicotinamide N-methyltransferase

NPC

Nasopharyngeal carcinoma

Notes

Acknowledgments

This work was supported by a grant from Chi Mei Medical Center

Conflicts of interest

None

References

  1. 1.
    Guigay J. Advances in nasopharyngeal carcinoma. Curr Opin Oncol. 2008;20:264–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:421–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Jia WH, Qin HD. Non-viral environmental risk factors for nasopharyngeal carcinoma: a systematic review. Semin Cancer Biol. 2012;22:117–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Lo KW, Huang DP. Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:451–62.PubMedCrossRefGoogle Scholar
  5. 5.
    Lee AW, Ng WT, Chan YH, Sze H, Chan C, Lam TH. The battle against nasopharyngeal cancer. Radiother Oncol. 2012;104:272–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rini J, Szumlanski C, Guerciolini R, Weinshilboum RM. Human liver nicotinamide N-methyltransferase: ion-pairing radiochemical assay, biochemical properties and individual variation. Clinica Chimica Acta; Int J Clin Chem. 1990;186:359–74.CrossRefGoogle Scholar
  7. 7.
    Aksoy S, Szumlanski CL, Weinshilboum RM. Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem. 1994;269:14835–40.PubMedGoogle Scholar
  8. 8.
    Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM. Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization. Genomics. 1995;29:555–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Green S, Buttrum S, Molloy H, Steventon G, Sturman S, Waring R, et al. N-methylation of pyridines in Parkinson’s disease. Lancet. 1991;338:120–1.PubMedCrossRefGoogle Scholar
  10. 10.
    Cuomo R, Dattilo M, Pumpo R, Capuano G, Boselli L, Budillon G. Nicotinamide methylation in patients with cirrhosis. J Hepatol. 1994;20:138–42.PubMedCrossRefGoogle Scholar
  11. 11.
    Debigare R, Maltais F, Cote CH, Michaud A, Caron MA, Mofarrahi M, et al. Profiling of mRNA expression in quadriceps of patients with COPD and muscle wasting. COPD. 2008;5:75–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Mateuszuk L, Khomich TI, Slominska E, Gajda M, Wojcik L, Lomnicka M, et al. Activation of nicotinamide N-methyltrasferase and increased formation of 1-methylnicotinamide (MNA) in atherosclerosis. Pharmacol Reports. 2009;61:76–85.Google Scholar
  13. 13.
    Markert JM, Fuller CM, Gillespie GY, Bubien JK, McLean LA, Hong RL, et al. Differential gene expression profiling in human brain tumors. Physiol Genom. 2001;5:21–33.Google Scholar
  14. 14.
    Jang JS, Cho HY, Lee YJ, Ha WS, Kim HW. The differential proteome profile of stomach cancer: identification of the biomarker candidates. Oncol Res. 2004;14:491–9.PubMedGoogle Scholar
  15. 15.
    Xu J, Moatamed F, Caldwell JS, Walker JR, Kraiem Z, Taki K, et al. Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells. J Clin Endocrinol Metab. 2003;88:4990–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Yao M, Tabuchi H, Nagashima Y, Baba M, Nakaigawa N, Ishiguro H, et al. Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol. 2005;205:377–87.PubMedCrossRefGoogle Scholar
  17. 17.
    Sartini D, Muzzonigro G, Milanese G, Pierella F, Rossi V, Emanuelli M. Identification of nicotinamide N-methyltransferase as a novel tumor marker for renal clear cell carcinoma. J Urol. 2006;176:2248–54.PubMedCrossRefGoogle Scholar
  18. 18.
    Sartini D, Santarelli A, Rossi V, Goteri G, Rubini C, Ciavarella D, et al. Nicotinamide N-methyltransferase upregulation inversely correlates with lymph node metastasis in oral squamous cell carcinoma. Mol Med. 2007;13:415–21.PubMedGoogle Scholar
  19. 19.
    Roessler M, Rollinger W, Palme S, Hagmann ML, Berndt P, Engel AM, et al. Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin Cancer Res. 2005;11:6550–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim J, Hong SJ, Lim EK, Yu YS, Kim SW, Roh JH, et al. Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exper ClinCancer Res. 2009;28:20.CrossRefGoogle Scholar
  21. 21.
    Wu Y, Siadaty MS, Berens ME, Hampton GM, Theodorescu D. Overlapping gene expression profiles of cell migration and tumor invasion in human bladder cancer identify metallothionein 1E and nicotinamide N-methyltransferase as novel regulators of cell migration. Oncogene. 2008;27:6679–89.PubMedCrossRefGoogle Scholar
  22. 22.
    Tomida M, Mikami I, Takeuchi S, Nishimura H, Akiyama H. Serum levels of nicotinamide N-methyltransferase in patients with lung cancer. J Cancer Res Clin Oncol. 2009;135:1223–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Rogers CD, Fukushima N, Sato N, Shi C, Prasad N, Hustinx SR, et al. Differentiating pancreatic lesions by microarray and QPCR analysis of pancreatic juice RNAs. Cancer Biol Ther. 2006;5:1383–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Franke TF. PI3K/Akt: getting it right matters. Oncogene. 2008;27:6473–88.PubMedCrossRefGoogle Scholar
  25. 25.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.PubMedCrossRefGoogle Scholar
  26. 26.
    Valerie K, Yacoub A, Hagan MP, Curiel DT, Fisher PB, Grant S, et al. Radiation-induced cell signaling: inside-out and outside-in. Mol Cancer Ther. 2007;6:789–801.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang L, Xing D, Gao X, Wu S. Low-power laser irradiation promotes cell proliferation by activating PI3K/Akt pathway. J Cell Physiol. 2009;219:553–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Tang SW, Yang TC, Lin WC, Chang WH, Wang CC, Lai MK, et al. Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells. Carcinogenesis. 2011;32:138–45.PubMedCrossRefGoogle Scholar
  29. 29.
    Kao YC, Lee SW, Lin LC, Chen LT, Hsing CH, Hsu HP, et al. Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma. Tumour Biol. 2013;34(2):759–68.PubMedCrossRefGoogle Scholar
  30. 30.
    Edge SB. In: Edge SB et al., editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  31. 31.
    Le QT, Tate D, Koong A, Gibbs IC, Chang SD, Adler JR, et al. Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2003;56:1046–54.PubMedCrossRefGoogle Scholar
  32. 32.
    Ogawa A, Griffin RJ, Song CW. Effect of a combination of mild-temperature hyperthermia and nicotinamide on the radiation response of experimental tumors. Radiat Res. 2000;153:327–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Sun LQ, Coucke PA, Mirimanoff RO, Buchegger F. Fractionated irradiation combined with carbogen breathing and nicotinamide of two human glioblastomas grafted in nude mice. Radiat Res. 2001;155:26–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol. 1996;6:10–21.PubMedCrossRefGoogle Scholar
  35. 35.
    Droller MJ. Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen and nicotinamide. J Urol. 2000;163:1600.PubMedGoogle Scholar
  36. 36.
    Clark JB, Ferris GM, Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5′-methyl nicotinamide. Biochim Biophys Acta. 1971;238:82–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Smith S. The world according to PARP. Trends Biochem Sci. 2001;26:174–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kassem H, Sangar V, Cowan R, Clarke N, Margison GP. A potential role of heat shock proteins and nicotinamide N-methyl transferase in predicting response to radiation in bladder cancer. Int J Cancer. 2002;101:454–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Li HF, Kim JS, Waldman T. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol. 2009;4:43.PubMedCrossRefGoogle Scholar
  40. 40.
    Xia S, Zhao Y, Yu S, Zhang M. Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells. Cancer Biother Radiopharm. 2010;25:317–23.PubMedCrossRefGoogle Scholar
  41. 41.
    Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96:2110–5.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Khin Than Win
    • 1
  • Sung-Wei Lee
    • 2
  • Hsuan-Ying Huang
    • 3
  • Li-Ching Lin
    • 4
  • Ching-Yih Lin
    • 5
    • 6
  • Chung-Hsi Hsing
    • 7
    • 8
  • Li-Tzong Chen
    • 9
    • 10
    • 11
  • Chien-Feng Li
    • 1
    • 9
    • 12
    • 13
  1. 1.Department of PathologyChi-Mei Medical CenterTainan CountyTaiwan
  2. 2.Department of Radiation OncologyChi-Mei Medical CenterTainanTaiwan
  3. 3.Department of Pathology, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
  4. 4.Department of Radiation OncologyChi-Mei Medical CenterTainanTaiwan
  5. 5.Division of Gastroenterology and Hepatology, Department of Internal MedicineChi-Mei Medical CenterTainanTaiwan
  6. 6.Department of Leisure, Recreation, and Tourism ManagementTainanTaiwan
  7. 7.Department of AnesthesiologyChi-Mei Medical CenterTainanTaiwan
  8. 8.Department of AnesthesiologyCollege of Medicine, Taipei Medical UniversityTainanTaiwan
  9. 9.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  10. 10.Department of Internal MedicineNational Cheng Kung University HospitalTainanTaiwan
  11. 11.Department of Internal Medicine and Cancer Center, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
  12. 12.Institute of Clinical MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  13. 13.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan

Personalised recommendations