Skip to main content
Log in

Prognostic significance of nemo-like kinase (NLK) expression in patients with gallbladder cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

Nemo-like kinase (NLK), a serine/threonine protein kinase, has been implicated in tumor development and progression, and plays an important role in diverse signaling pathways by phosphorylating a variety of transcription factors. Recent studies demonstrated that altered expression of NLK was observed in various types of human cancers. However, the clinical significance of NLK expression in gallbladder cancer (GBC) remains largely unknown. In this study, we focused on the clinical significance of NLK in GBC, and found that nuclear NLK protein overexpression was frequently detected in GBC tissues. The overexpression of NLK was significantly correlated with histological grade, TNM stage, and perineural invasion. The results of Kaplan–Meier analysis indicated that a high expression level of NLK resulted in a significantly poorer prognosis of GBC patients (P = 0.002). Furthermore, multivariate Cox regression analysis showed that high NLK expression was an independent prognostic factor for GBC patients (HR = 3.077). In conclusion, overexpression of NLK is closely related to progression of GBC, and NLK could be used as a potential prognostic marker for GBC patients.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.

    Article  PubMed  CAS  Google Scholar 

  2. Li M, Shen J, Wu X, Zhang B, Zhang R, Weng H, et al. Downregulated expression of hepatoma-derived growth factor (HDGF) reduces gallbladder cancer cell proliferation and invasion. Med Oncol. 2013;30:587. doi:10.1007/s12032-013-0587-7.

    Article  PubMed  CAS  Google Scholar 

  3. Boutros C, Gary M, Baldwin K, Somasundar P. Gallbladder cancer: past, present and an uncertain future. Surg Oncol. 2012;21:e183–91.

    Article  PubMed  CAS  Google Scholar 

  4. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.

    Article  PubMed  CAS  Google Scholar 

  5. Obara Y, Nakahata N. The signaling pathway leading to extracellular signal-regulated kinase 5 (ERK5) activation via G-proteins and ERK5-dependent neurotrophic effects. Mol Pharmacol. 2010;77:10–6.

    Article  PubMed  CAS  Google Scholar 

  6. Mendes-Pereira AM, Lord CJ, Ashworth A. NLK is a novel therapeutic target for PTEN deficient tumour cells. PLoS One. 2012;7:e47249.

    Article  PubMed  CAS  Google Scholar 

  7. Li Z, Cui G, Wang J, Yu Z, Zhao L, Lv Z. Nemo-like Kinase (NLK) involves in neuronal apoptosis after traumatic brain injury. Cell Mol Neurobiol. 2012;32:381–9.

    Article  PubMed  Google Scholar 

  8. Ota S, Ishitani S, Shimizu N, Matsumoto K, Itoh M, Ishitani T. NLK positively regulates Wnt/β- catenin signalling by phosphorylating LEF1 in neural progenitor cells. EMBO J. 2012;31:1904–15.

    Article  PubMed  CAS  Google Scholar 

  9. Tan Z, Li M, Wu W, Zhang L, Ding Q, Wu X, et al. NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells. Mol Cell Biochem. 2012;369:27–33.

    Article  PubMed  CAS  Google Scholar 

  10. Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Archiv. 2008;452:139–46.

    Article  PubMed  CAS  Google Scholar 

  11. Quan Z, Gu J, Dong P, Lu J, Wu X, Wu W, et al. Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to cirsimaritin-induced apoptosis in human gallbladder carcinoma GBC-SD cells. Cancer Lett. 2010;295:252–9.

    Article  PubMed  CAS  Google Scholar 

  12. Srivastava K, Srivastava A, Sharma KL, Mittal B. Candidate gene studies in gallbladder cancer: a systematic review and meta-analysis. Mutat Res. 2011;728:67–79.

    Article  PubMed  CAS  Google Scholar 

  13. Ishitani T, Ishitani S. Nemo-like kinase, a multifaceted cell signaling regulator. Cell Signal. 2013;25:190–7.

    Article  PubMed  CAS  Google Scholar 

  14. Ishitani T. Context-dependent dual and opposite roles of nemo-like kinase in the Wnt/β-catenin signaling. Cell Cycle. 2012;11:1743–5.

    Article  PubMed  CAS  Google Scholar 

  15. Yasuda J, Yokoo H, Yamada T, Kitabayashi I, Sekiya T, Ichikawa H. Nemo–like kinase suppresses a wide range of transcription factors, including nuclear factor–kB. Cancer Sci. 2004;95:52–7.

    Article  PubMed  CAS  Google Scholar 

  16. Zanotti S, Canalis E. Nemo–like kinase inhibits osteoblastogenesis by suppressing bone morphogenetic protein and WNT canonical signaling. J Cell Biochem. 2012;113:449–56.

    Article  PubMed  CAS  Google Scholar 

  17. Ota R, Kotani T, Yamashita M. Possible involvement of nemo-like kinase 1 in Xenopus oocyte maturation as a kinase responsible for Pumilio1, Pumilio2, and CPEB phosphorylation. Biochemistry. 2011;50:5648–59.

    Article  PubMed  CAS  Google Scholar 

  18. Togi S, Ikeda O, Kamitani S, Nakasuji M, Sekine Y, Muromoto R, et al. Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/β-Catenin signaling through interaction with nemo-like Kinase and T cell factor 4 (NLK/TCF4). J Biol Chem. 2011;286:19170–7.

    Article  PubMed  CAS  Google Scholar 

  19. Yasuda J, Tsuchiya A, Yamada T, Sakamoto M, Sekiya T, Hirohashi S. Nemo-like kinase induces apoptosis in DLD-1 human colon cancer cells. Biochem Biophys Res Commun. 2003;308:227–33.

    Article  PubMed  CAS  Google Scholar 

  20. Emami KH, Brown LG, Pitts TE, Sun X, Vessella RL, Corey E. Nemo–like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate. 2009;69:1481–92.

    Article  PubMed  CAS  Google Scholar 

  21. Cui G, Li Z, Shao B, Zhao L, Zhou Y, Lu T, et al. Clinical and biological significance of Nemo-like kinase expression in glioma. J Clin Neurosci. 2011;18:271–5.

    Article  PubMed  CAS  Google Scholar 

  22. Jung KH, Kim JK, Noh JH, Eun JW, Bae HJ, Xie HJ, et al. Targeted disruption of Nemo–like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma. J Cell Biochem. 2010;110:687–96.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Xinhua hospital (No. 12YJ01), the Shanghai Committee of Science and Technology (Nos. 12JC1406700, 12410705900, 12401905800), the National Natural Science Foundation of China (Nos. 81172029, 81272402), the Foundation of Shanghai Outstanding Academic Leaders (No.11XD1403800), the National High Technology Research and Development Program (863 Program; No.2012AA022606), and the Medical and Engineering Cross-Foundation of Shanghai Jiaotong University (No. YG2011ZD07).

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yingbin Liu.

Additional information

Maolan Li and Shenglai Zhang, contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, M., Zhang, S., Wang, Z. et al. Prognostic significance of nemo-like kinase (NLK) expression in patients with gallbladder cancer. Tumor Biol. 34, 3995–4000 (2013). https://doi.org/10.1007/s13277-013-0988-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-013-0988-4

Keywords

Navigation