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.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12032-014-0317-9/MediaObjects/12032_2014_317_Fig1_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12032-014-0317-9/MediaObjects/12032_2014_317_Fig2_HTML.gif)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs12032-014-0317-9/MediaObjects/12032_2014_317_Fig3_HTML.gif)
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
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.
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.
Enzinger PC, Mayer RJ. Esophageal cancer. New Engl J Med. 2003;349(23):2241–52.
Siyanova EY, Serfas MS, Mazo IA, Tyner AL. Tyrosine kinase gene expression in the mouse small intestine. Oncogene. 1994;9(7):2053–7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ostrander JH, Daniel AR, Lange CA. Brk/PTK6 signaling in normal and cancer cell models. Curr Opin Pharmacol. 2010;10(6):662–9.
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.
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.
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
Corresponding author
Additional information
You-Fang Chen and Gang Ma contributed equally to the work as first author.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-014-0317-9