Skip to main content

Advertisement

SpringerLink
Log in

Nicotinamide N-Methyltransferase Expression in High-Grade Serous Carcinoma and Its Association with Survival

  • Original Article
  • Published:
Indian Journal of Gynecologic Oncology Aims and scope Submit manuscript

Abstract

Introduction

Ovarian cancer is the most lethal gynecological malignancy. Mechanisms involved in the progression of primary high-grade serous carcinoma (HGSC) into metastatic carcinoma are not understood. Nicotinamide N-methyltransferase (NNMT) is overexpressed in cancer, and its overexpression leads to epigenetic changes through hypomethylation of histones. It plays a role in epithelial–mesenchymal transition and sustenance of cancer stem cells. NNMT expression in primary and metastases of ovarian carcinoma and its relationship with survival have not been studied before.

Materials and Methods

We compared the expression of NNMT between primary and matched synchronous metastatic carcinoma of patients, diagnosed with HGSC. Benign ovarian and omental tissues were used as controls. The relationships between NNMT expression and relapse-free and disease-specific survival were analyzed.

Results

NNMT expression in metastases was significantly higher than matched primary carcinoma. NNMT was overexpressed in the stroma of primary and metastatic tumors. Increased NNMT expression was associated with decreased relapse-free and disease-specific survival.

Conclusion

This study detected a higher expression of NNMT in metastases of HGSC compared to matched primary and associated increased metastatic NNMT expression with decreased survival. Upregulation of NNMT in tumor stroma suggests it plays a role in desmoplasia. Targeting of NNMT and desmoplasia may play a critical role in the treatment of HGSC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  Google Scholar 

  2. Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med. 2009;361:170–7.

    Article  CAS  Google Scholar 

  3. Brodsky AS, Fischer A, Miller DH, Vang S, MacLaughlan S, Wu HT, Yu J, Steinhoff M, Collins C, Smith PJ, Raphael BJ, Brard L. Expression profiling of primary and metastatic ovarian tumors reveals differences indicative of aggressive disease. PLoS ONE. 2014;9(4):e94476. https://doi.org/10.1371/journal.pone.0094476.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bignotti E, Tassi RA, Calza S, Ravaggi A, Bandiera E, Rossi E, Donzelli C, Pasinetti B, Pecorelli S, Santin AD. Gene expression profile of ovarian serous papillary carcinomas: identification of metastasis-associated genes. Am J Obstet Gynecol. 2007;196(3):245.e1–11.

    Article  Google Scholar 

  5. Kanska J, Aspuria PP, Taylor-Harding B, et al. Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT. Oncotarget. 2017;8(16):26200–20. https://doi.org/10.18632/oncotarget.15429.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol. 2013;9(5):300–6. https://doi.org/10.1038/nchembio.1204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen C, Wang X, Huang X, et al. Nicotinamide N-methyltransferase: a potential biomarker for worse prognosis in gastric carcinoma. Am J Cancer Res. 2016;6(3):649–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Xie X, Liu H, Wang Y, et al. Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway. Oncotarget. 2016;7(29):45837–48. https://doi.org/10.18632/oncotarget.9962.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xu Y, Liu P, Zheng DH, et al. Expression profile and prognostic value of NNMT in patients with pancreatic cancer. Oncotarget. 2016;7(15):19975–81. https://doi.org/10.18632/oncotarget.7891.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sartini D, Seta R, Pozzi V, et al. Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity. Biol Chem. 2015;396(3):225–34. https://doi.org/10.1515/hsz-2014-0231.

    Article  CAS  PubMed  Google Scholar 

  11. Palanichamy K, Kanji S, Gordon N, et al. NNMT silencing activates tumor suppressor PP2A, inactivates oncogenic STKs, and inhibits tumor forming ability. Clin Cancer Res. 2017;23(9):2325–34. https://doi.org/10.1158/1078-0432.CCR-16-1323.

    Article  CAS  PubMed  Google Scholar 

  12. Liang L, Zeng M, Pan H, Liu H, He Y. Nicotinamide N-methyltransferase promotes epithelial-mesenchymal transition in gastric cancer cells by activating transforming growth factor-β1 expression. Oncol Lett. 2018;15(4):4592–8. https://doi.org/10.3892/ol.2018.7885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pozzi V, Sartini D, Rocchetti R, et al. Identification and characterization of cancer stem cells from head and neck squamous cell carcinoma cell lines. Cell Physiol Biochem. 2015;36(2):784–98. https://doi.org/10.1159/000430138.

    Article  CAS  PubMed  Google Scholar 

  14. Kurman RJ, Carcangiu ML, Herrington CS, et al. editors. WHO classification of tumours of female reproductive organs. In: WHO classification of tumours, vol 4. Aufl. Lyon: WHO Press; 2014.

  15. Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet. 2014;124(1):1–5.

    Article  Google Scholar 

  16. Singh N, Gilks CB, Wilkinson N, et al. Assessment of a new system for primary site assignment in high-grade serous carcinoma of the fallopian tube, ovary, and peritoneum. Histopathology. 2015;67:331–7.

    Article  Google Scholar 

  17. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet. 1382P;374:1371–1382P.J.

    Article  CAS  Google Scholar 

  18. Albini A, Bruno A, Gallo C, Pajardi G, Noonan DM, Dallaglio K. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity. Connect Tissue Res. 2015;56(5):414–25. https://doi.org/10.3109/03008207.2015.1066780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Campagna R, Cecati M, Pozzi V, Fumarola S, Pompei V, Milanese G, Galosi AB, Sartini D, Emanuelli M. Involvement of transforming growth factor beta 1 in the transcriptional regulation of nicotinamide N-methyltransferase in clear cell renal cell carcinoma. Cell Mol Biol (Noisy-le-grand). 2018;64(7):51–5.

    Article  Google Scholar 

  20. Tothill RW, Tinker AV, George J, Brown R, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14(16):5198–208. https://doi.org/10.1158/1078-0432.CCR-08-0196.

    Article  CAS  PubMed  Google Scholar 

  21. Doraiswamy V, Parrott JA, Skinner MK. Expression and action of transforming growth factor alpha in normal ovarian surface epithelium and ovarian cancer. Biol Reprod. 2000;63:789–96.

    Article  CAS  Google Scholar 

  22. Nilsson E, Doraiswamy V, Parrott JA, Skinner MK. Expression and action of transforming growth factor beta (TGFbeta1, TGFbeta2, TGFbeta3) in normal bovine ovarian surface epithelium and implications for human ovarian cancer. Mol Cell Endocrinol. 2001;182:145–55.

    Article  CAS  Google Scholar 

  23. Whatcott CJ, Diep CH, Jiang P, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015;21(15):3561–8.

    Article  CAS  Google Scholar 

  24. Moran-Jones K, Gloss BS, Murali R, et al. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer. Oncotarget. 2015;6(42):44551–62. https://doi.org/10.18632/oncotarget.6082.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim J, Hong SJ, Lim EK, et al. Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exp Clin Cancer Res. 2009;16(28):20. https://doi.org/10.1186/1756-9966-28-20.

    Article  CAS  Google Scholar 

  26. Liu X, Fan D. The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. Curr Pharm Des. 2015;21(10):1279–91.

    Article  CAS  Google Scholar 

  27. Jung J, Kim LJY, Wang X, Wu Q, Sanvoranart T, Hubert CG, Prager BC, Wallace LC, Jin X, Mack SC, Rich JN. Nicotinamide metabolism regulates glioblastoma stem cell maintenance. JCI Insight. 2017;2(10):pii: 90019. https://doi.org/10.1172/jci.insight.90019.

    Article  Google Scholar 

  28. Kwon MJ, Shin YK. Regulation of ovarian cancer stem cells or tumor-initiating cells. Int J Mol Sci. 2013;14(4):6624–48. https://doi.org/10.3390/ijms14046624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The study was funded by Scientific Research endorsement (#18401135).

Author information

Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Selcuk University Medical School, 60615, Konya, Turkey

    Serra Akar & Çetin Çelik

  2. Department of Pathology, Selcuk University Medical School, Konya, Turkey

    İsmail Harmankaya & Serdar Uğraş

Authors
  1. Serra Akar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. İsmail Harmankaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Serdar Uğraş
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Çetin Çelik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Serra Akar.

Ethics declarations

Conflict of interest

The authors report no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akar, S., Harmankaya, İ., Uğraş, S. et al. Nicotinamide N-Methyltransferase Expression in High-Grade Serous Carcinoma and Its Association with Survival. Indian J Gynecol Oncolog 17, 82 (2019). https://doi.org/10.1007/s40944-019-0327-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40944-019-0327-9

Keywords

Search

Navigation