Tumor Biology

, Volume 36, Issue 8, pp 6181–6189 | Cite as

Prognostic significance of Ku80 in pT2N0M0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy

  • Shuai Wang
  • Zhou Wang
  • Xiangyan Liu
  • Yu Yang
  • Mo Shi
  • Zhenguo Sun
Research Article

Abstract

Recent studies have shown that Ku80, a DNA repair protein, was involved in progression of malignant tumors. This study aimed to clarify the clinicopathological significance and prognostic value of Ku80 in pT2N0M0 esophageal squamous cell carcinoma (ESCC). We enrolled 217 patients with pT2N0M0 midthoracic ESCC who had undergone Ivor-Lewis esophagectomy. The expression profile of Ku80 was examined by immunohistochemistry. The results were correlated with the clinicopathological variables, overall survival (OS) and disease-free survival (DFS), in pT2N0M0 ESCC patients. The expression of Ku80 were higher in ESCC tissues than the corresponding health esophageal mucosa (P < 0.001). Clinically, the Ku80 expression levels were significantly related to tumor size (P = 0.018), differentiation degree (P = 0.010), and tumor-node-metastasis (TNM) stage (P = 0.001). Subsequent multivariate analysis demonstrated that tumor size, differentiation degree, TNM stage, and Ku80 expression were independent prognostic factors for the OS and the DFS of pT2N0M0 ESCC patients. Our data indicated that Ku80 expression level associates with key clinicopathological features and is an independent predictor of the OS and the DFS in pT2N0M0 ESCC patients.

Keywords

Prognosis Ku80 Esophageal squamous cell carcinoma Esophagectomy 

Notes

Conflicts of interest

None

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. Estimates of worldwide burden of cancer in 2008. GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917. doi: 10.1002/ijc.25516.CrossRefPubMedGoogle Scholar
  2. 2.
    Mariette C, Piessen G, Triboulet JP. Therapeutic strategies in oesophageal carcinoma: role of surgery and other modalities. Lancet Oncol. 2007;8:545–53.CrossRefPubMedGoogle Scholar
  3. 3.
    Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–50.CrossRefPubMedGoogle Scholar
  4. 4.
    D’Annoville T, D’Journo XB, Loundou A, Trousse D, Dahan L, et al. Prognostic impact of the extracapsular lymph node involvement on disease-free survival according to the 7th edition of American Joint Committee on Cancer Staging System. Eur J Cardiothorac Surg. 2013;44:e207–11. doi: 10.1093/ejcts/ezt332.CrossRefPubMedGoogle Scholar
  5. 5.
    Hou X, Wei JC, Fu JH, Wang X, Zhang LJ, et al. Proposed modification of the seventh American Joint Committee on Cancer staging system for esophageal squamous cell carcinoma in Chinese patients. Ann Surg Oncol. 2014;21:337–42. doi: 10.1245/s10434-013-3265-2.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen G, Wang Z, Liu XY, Liu FY. Adjuvant radiotherapy after modified Ivor-Lewis esophagectomy: can it prevent lymph node recurrence of the mid-thoracic esophageal carcinoma? Ann Thorac Surg. 2009;87:1697–702. doi: 10.1016/j.athoracsur.2009.03.060.CrossRefPubMedGoogle Scholar
  7. 7.
    Song Y, Wang Z, Liu X, Jiang W, Shi M. CCR7 and VEGF-C: molecular indicator of lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma after Ivor-Lewis esophagectomy? Ann Surg Oncol. 2012;19:3606–12. doi: 10.1245/s10434-012-2419-y.CrossRefPubMedGoogle Scholar
  8. 8.
    Kamangar F, Chow WH, Abnet CC, Dawsey SM. Environmental causes of esophageal cancer. Gastroenterol Clin North Am. 2009;38:27–57. doi: 10.1016/j.gtc.2009.01.004.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Tuteja R, Tuteja N. Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol. 2000;35:1–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Tong WM, Cortes U, Hande MP, Ohgaki H, Cavalli LR, et al. Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Cancer Res. 2002;62:6990–6.PubMedGoogle Scholar
  11. 11.
    Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 2000;404:897–900.CrossRefPubMedGoogle Scholar
  12. 12.
    Groselj B, Kerr M, Kiltie AE. Radiosensitisation of bladder cancer cells by panobinostat is modulated by Ku80 expression. Radiother Oncol. 2013;108:429–33. doi: 10.1016/j.radonc.2013.06.021.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kruer TL, Cummins TD, Powell DW, Wittliff JL. Characterization of estrogen response element binding proteins as biomarkers of breast cancer behavior. Clin Biochem. 2013;46:1739–46. doi: 10.1016/j.clinbiochem.2013.07.005.CrossRefPubMedGoogle Scholar
  14. 14.
    Lim JW, Kim H, Kim KH. Expression of Ku70 and Ku80 mediated by NF-kappa B and cyclooxygenase-2 is related to proliferation of human gastric cancer cells. J Biol Chem. 2002;277:46093–100.CrossRefPubMedGoogle Scholar
  15. 15.
    Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y, Enomoto A, et al. Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol. 2004;25:461–8.PubMedGoogle Scholar
  16. 16.
    Yang QS, Gu JL, Du LQ, Jia LL, Qin LL, et al. ShRNA-mediated Ku80 gene silencing inhibits cell proliferation and sensitizes to gamma-radiation and mitomycin C-induced apoptosis in esophageal squamous cell carcinoma lines. J Radiat Res. 2008;49:399–407.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen G, Wang Z, Liu XY, Zhang MY, Liu FY. Clinical study of modified Ivor-Lewis esophagectomy plus adjuvant radiotherapy for local control of stage IIA squamous cell carcinoma in the midthoracic esophagus. Eur J Cardiothorac Surg. 2009;35:1–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.Google Scholar
  19. 19.
    Koike M, Shiomi T, Koike A. Dimerization and nuclear localization of ku proteins. J Biol Chem. 2001;276:11167–73.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang Z, Liu XY, Liu FY, Chen JH. A study of correlation between early postoperative relapse with lymph node micrometastasis in patients with N0 esophageal cancer. Zhonghua Wai Ke Za Zhi. 2004;42:68–71.PubMedGoogle Scholar
  21. 21.
    Ma Q, Li P, Xu M, Yin J, Su Z, et al. Ku80 is highly expressed in lung adenocarcinoma and promotes cisplatin resistance. J Exp Clin Cancer Res. 2012;31:99. doi: 10.1186/1756-9966-31-99.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Alshareeda AT, Negm OH, Albarakati N, Green AR, Nolan C, et al. Clinicopathological significance of KU70/KU80, a key DNA damage repair protein in breast cancer. Breast Cancer Res Treat. 2013;139:301–10. doi: 10.1007/s10549-013-2542-x.CrossRefPubMedGoogle Scholar
  23. 23.
    Soderlund Leifler K, Queseth S, Fornander T, Askmalm MS. Low expression of Ku70/80, but high expression of DNAPKcs, predict good response to radiotherapy in early breast cancer. Int J Oncol. 2010;37:1547–54.PubMedGoogle Scholar
  24. 24.
    Grabsch H, Dattani M, Barker L, Maughan N, Maude K, et al. Expression of DNA double-strand break repair proteins ATM and BRCA1 predicts survival in colorectal cancer. Clin Cancer Res. 2006;12:1494–500.CrossRefPubMedGoogle Scholar
  25. 25.
    Komuro Y, Watanabe T, Hosoi Y, Matsumoto Y, Nakagawa K, et al. The expression pattern of Ku correlates with tumor radiosensitivity and disease free survival in patients with rectal carcinoma. Cancer. 2002;95:1199–205.CrossRefPubMedGoogle Scholar
  26. 26.
    Monferran S, Paupert J, Dauvillier S, Salles B, Muller C. The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase 9. EMBO J. 2004;23:3758–68.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Teoh G, Urashima M, Greenfield EA, Nguyen KA, Lee JF, et al. The 86-kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells. J Clin Invest. 1998;101:1379–88.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Muller C, Paupert J, Monferran S, Salles B. The double life of the Ku protein: facing the DNA breaks and the extracellular environment. Cell Cycle. 2005;4:438–41.CrossRefPubMedGoogle Scholar
  29. 29.
    Aleskandarany M, Caracappa D, Nolan CC, Macmillan RD, Ellis IO, et al. DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Res Treat. 2015;150:81–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Green AR, Caracappa D, Benhasouna AA, Alshareeda A, Nolan CC, et al. Biological and clinical significance of PARP1 protein expression in breast cancer. Breast Cancer Res Treat. 2015;149:353–62.CrossRefPubMedGoogle Scholar
  31. 31.
    Lu Y, Gao J, Lu Y. Downregulated Ku70 and ATM associated to poor prognosis in colorectal cancer among Chinese patients. Oncol Targets Ther. 2014;7:1955–61.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shuai Wang
    • 1
  • Zhou Wang
    • 1
  • Xiangyan Liu
    • 1
  • Yu Yang
    • 2
  • Mo Shi
    • 1
  • Zhenguo Sun
    • 1
  1. 1.Department of Thoracic SurgeryProvincial Hospital Affiliated to Shandong UniversityJinanPeople’s Republic of China
  2. 2.Department of PathologyProvincial Hospital Affiliated to Shandong UniversityJinanPeople’s Republic of China

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