Log in

Downregulated expression of PTK6 is correlated with poor survival in esophageal squamous cell carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

To investigate the clinical prognostic value of protein tyrosine kinase 6 (PTK6) in patients with esophageal squamous cell carcinoma (ESCC), quantitative RT-PCR and Western blotting were utilized to measure the mRNA and protein expression levels of PTK6 in 29 and eight pairs of ESCC and peritumoral normal esophageal tissues, respectively. Furthermore, the expression of PTK6 protein in 210 ESCCs was examined with immunohistochemistry (IHC), and its clinical value was analyzed using Kaplan–Meier plots and the Cox proportional hazards regression model. The results found that the expression levels of both PTK6 mRNA and protein in ESCC tissues were significantly lower than those in peritumoral normal esophageal tissues. Regarding the IHC analysis of ESCC, the cytoplasmic expression of PTK6 was significantly correlated with tumor grade (P < 0.001). Compared with patients with low PTK6 expression, ESCC patients with overexpression of PTK6 displayed preferable disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P = 0.001, respectively), especially in stage II disease (P = 0.002 and P = 0.021, respectively). PTK6 was evaluated as an independent prognostic factor for ESCC using multivariate Cox regression analysis. All data demonstrated that the expression level of PTK6 is an independent prognostic factor in ESCCs. Low expression of PTK6 is correlated with poor DFS and OS in ESCCs.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Guo P, Li K. Trends in esophageal cancer mortality in China during 1987–2009: age, period and birth cohort analyzes. Cancer Epidemiol. 2012;36(2):99–105.

    Article  PubMed  Google Scholar 

  3. Tran GD, Sun XD, Abnet CC, Fan JH, Dawsey SM, Dong ZW, et al. Prospective study of risk factors for esophageal and gastric cancers in the Linxian general population trial cohort in China. Int J Cancer. 2005;113(3):456–63.

    Article  CAS  PubMed  Google Scholar 

  4. Enzinger PC, Mayer RJ. Esophageal cancer. New Engl J Med. 2003;349(23):2241–52.

    Article  CAS  PubMed  Google Scholar 

  5. Siyanova EY, Serfas MS, Mazo IA, Tyner AL. Tyrosine kinase gene expression in the mouse small intestine. Oncogene. 1994;9(7):2053–7.

    CAS  PubMed  Google Scholar 

  6. Vasioukhin V, Tyner AL. A role for the epithelial-cell-specific tyrosine kinase Sik during keratinocyte differentiation. Proc Natl Acad Sci USA. 1997;94(26):14477–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Derry JJ, Prins GS, Ray V, Tyner AL. Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells. Oncogene. 2003;22(27):4212–20.

    Article  CAS  PubMed  Google Scholar 

  8. Petro BJ, Tan RC, Tyner AL, Lingen MW, Watanabe K. Differential expression of the non-receptor tyrosine kinase BRK in oral squamous cell carcinoma and normal oral epithelium. Oral Oncol. 2004;40(10):1040–7.

    Article  CAS  PubMed  Google Scholar 

  9. Kasprzycka M, Majewski M, Wang ZJ, Ptasznik A, Wysocka M, Zhang Q, et al. Expression and oncogenic role of Brk (PTK6/Sik) protein tyrosine kinase in lymphocytes. Am J Pathol. 2006;168(5):1631–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Llor X, Serfas MS, Bie W, Vasioukhin V, Polonskaia M, Derry J, et al. BRK/Sik expression in the gastrointestinal tract and in colon tumors. Clin Cancer Res. 1999;5(7):1767–77.

    CAS  PubMed  Google Scholar 

  11. Vasioukhin V, Serfas MS, Siyanova EY, Polonskaia M, Costigan VJ, Liu B, et al. A novel intracellular epithelial cell tyrosine kinase is expressed in the skin and gastrointestinal tract. Oncogene. 1995;10(2):349–57.

    CAS  PubMed  Google Scholar 

  12. Locatelli A, Lofgren KA, Daniel AR, Castro NE, Lange CA. Mechanisms of HGF/Met signaling to Brk and Sam68 in breast cancer progression. Horm Cancer. 2012;3(1–2):14–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Schmandt RE, Bennett M, Clifford S, Thornton A, Jiang F, Broaddus RR, et al. The BRK tyrosine kinase is expressed in high-grade serous carcinoma of the ovary. Cancer Biol Ther. 2006;5(9):1136–41.

    Article  CAS  PubMed  Google Scholar 

  14. Haegebarth A, Nunez R, Tyner AL. The intracellular tyrosine kinase Brk sensitizes non-transformed cells to inducers of apoptosis. Cell Cycle. 2005;4(9):1239–46.

    Article  CAS  PubMed  Google Scholar 

  15. Ludyga N, Anastasov N, Gonzalez-Vasconcellos I, Ram M, Hofler H, Aubele M. Impact of protein tyrosine kinase 6 (PTK6) on human epidermal growth factor receptor (HER) signalling in breast cancer. Mol BioSyst. 2011;7(5):1603–12.

    Article  CAS  PubMed  Google Scholar 

  16. Liu XK, Zhang XR, Zhong Q, Li MZ, Liu ZM, Lin ZR, et al. Low expression of PTK6/Brk predicts poor prognosis in patients with laryngeal squamous cell carcinoma. J Transl Med. 2013;11:59.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Zhao C, Chen Y, Zhang W, Zhang J, Xu Y, Li W, et al. Expression of protein tyrosine kinase 6 (PTK6) in nonsmall cell lung cancer and their clinical and prognostic significance. Onco Targets Ther. 2013;6:183–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Liu LN, Huang PY, Lin ZR, Hu LJ, Liang JZ, Li MZ, et al. Protein tyrosine kinase 6 is associated with nasopharyngeal carcinoma poor prognosis and metastasis. J Transl Med. 2013;11:140.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Easty DJ, Mitchell PJ, Patel K, Florenes VA, Spritz RA, Bennett DC. Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma. Int J Cancer. 1997;71(6):1061–5.

    Article  CAS  PubMed  Google Scholar 

  20. Haegebarth A, Perekatt AO, Bie W, Gierut JJ, Tyner AL. Induction of protein tyrosine kinase 6 in mouse intestinal crypt epithelial cells promotes DNA damage-induced apoptosis. Gastroenterology. 2009;137(3):945–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Haegebarth A, Bie W, Yang R, Crawford SE, Vasioukhin V, Fuchs E, et al. Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine. Mol Cell Biol. 2006;26(13):4949–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Lofgren KA, Ostrander JH, Housa D, Hubbard GK, Locatelli A, Bliss RL, et al. Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK. Breast Cancer Res. 2011;13(5):R89.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Li X, Lu Y, Liang K, Hsu JM, Albarracin C, Mills GB, et al. Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. Oncogene. 2012;31(40):4372–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Aubele M, Auer G, Walch AK, Munro A, Atkinson MJ, Braselmann H, et al. PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas. Br J Cancer. 2007;96(5):801–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Aubele M, Walch AK, Ludyga N, Braselmann H, Atkinson MJ, Luber B, et al. Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients. Br J Cancer. 2008;99(7):1089–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Luo H, Yang Y, Huang F, Li F, Jiang Q, Shi K, et al. Selenite induces apoptosis in colorectal cancer cells via AKT-mediated inhibition of beta-catenin survival axis. Cancer Lett. 2012;315(1):78–85.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang P, Ostrander JH, Faivre EJ, Olsen A, Fitzsimmons D, Lange CA. Regulated association of protein kinase B/Akt with breast tumor kinase. J Biol Chem. 2005;280(3):1982–91.

    Article  CAS  PubMed  Google Scholar 

  28. Ma S, Bao JY, Kwan PS, Chan YP, Tong CM, Fu L, et al. Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma. Gastroenterology. 2012;143(3):675–86 e1–12.

  29. Cao X, Li Y, Luo RZ, He LR, Yang J, Zeng MS, et al. Tyrosine-protein phosphatase nonreceptor type 12 is a novel prognostic biomarker for esophageal squamous cell carcinoma. Ann Thora Surg. 2012;93(5):1674–80.

    Article  Google Scholar 

  30. Fermento ME, Gandini NA, Lang CA, Perez JE, Maturi HV, Curino AC, et al. Intracellular distribution of p300 and its differential recruitment to aggresomes in breast cancer. Exp Mol Pathol. 2010;88(2):256–64.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang S, Li Y, Zhu YH, Wu XQ, Tang J, Li Z, et al. Intensive expression of UNC-51-like kinase 1 is a novel biomarker of poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Sci. 2011;102(8):1568–75.

    Article  CAS  PubMed  Google Scholar 

  32. Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. New Engl J Med. 2006;355(10):983–91.

    Article  CAS  PubMed  Google Scholar 

  33. Ostrander JH, Daniel AR, Lange CA. Brk/PTK6 signaling in normal and cancer cell models. Curr Opin Pharmacol. 2010;10(6):662–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Brauer PM, Zheng Y, Wang L, Tyner AL. Cytoplasmic retention of protein tyrosine kinase 6 promotes growth of prostate tumor cells. Cell Cycle. 2010;9(20):4190–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Gaur P, Hofstetter WL, Bekele BN, Correa AM, Mehran RJ, Rice DC, et al. Comparison between established and the Worldwide Esophageal Cancer Collaboration staging systems. Ann Thorac Surg. 2010;89(6):1797–803, 1804 e1–3; discussion 1803–4.

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (Grant Number 81372568).

Conflict of interest

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhe-Sheng Wen.

Additional information

You-Fang Chen and Gang Ma contributed equally to the work as first author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, YF., Ma, G., Cao, X. et al. Downregulated expression of PTK6 is correlated with poor survival in esophageal squamous cell carcinoma. Med Oncol 31, 317 (2014). https://doi.org/10.1007/s12032-014-0317-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0317-9

Keywords

Navigation