Tumor Biology

, Volume 37, Issue 6, pp 7405–7412 | Cite as

The clinical utility of the proliferating cell nuclear antigen expression in patients with hepatocellular carcinoma

  • Shuangshuang Ma
  • Junsheng Yang
  • Jinpeng Li
  • Jinlong Song
Original Article


Proliferating cell nuclear antigen (PCNA) has been suggested as a potential diagnostic biomarker for early hepatocellular carcinoma (HCC). However, its prognostic significance in HCC remains unclear. In the present study, we investigated the expression and significance of PCNA in HCC and then analyzed the role of PCNA in clinical outcomes. Our findings show that the expression intensity of PCNA is much higher in HCC tissues than that in paracarcinoma tissues and associated with AFP, albumin, tumor number, clinical grade, vascular invasion, and tumor-node-metastasis (TNM) stage (all p < 0.000). Kaplan-Meier analysis indicated that high PCNA expression was associated with poor disease-free survival (DFS) (p < 0.000) and overall survival (OS) (p < 0.000) in a training cohort of 76 HCC patients. Multiple Cox regression analysis indicated PCNA acts as an independent predictor for DFS (p = 0.002) and OS (p = 0.004) in HCC patients. Along with pathological results, our systematic review also identified the expression of PCNA was closely associated with DFS and OS (both p < 0.000). In conclusion, this study suggested that PCNA is increased in HCC patients and is indeed a novel unfavorable biomarker for prognostic prediction for patients with this deadly disease.


PCNA HCC Clinical utility 



We greatly thank other members of our lab for valuable suggestions and writing.

Compliance with ethical standards

This study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute and complied with the Declaration of Helsinki. All of the patients provided written informed consent.


  1. 1.
    Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385(9972):977–1010.CrossRefPubMedGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedGoogle Scholar
  3. 3.
    Li XP, Cao GW, Sun Q, Yang C, Yan B, Zhang MY, et al. Cancer incidence and patient survival rates among the residents in the Pudong New Area of Shanghai between 2002 and 2006. Chin J Cancer. 2013;32(9):512–9.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Altekruse SF, Henley SJ, Cucinelli JE, McGlynn KA. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am J Gastroenterol. 2014;109(4):542–53.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Stoimenov I, Helleday T. PCNA on the crossroad of cancer. Biochem Soc Trans. 2009;37(Pt 3):605–13.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006;8(12):1359–68.CrossRefPubMedGoogle Scholar
  7. 7.
    Li Y, Dowbenko D, Lasky LA. AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem. 2002;277(13):11352–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Naryzhny SN, Lee H. The post-translational modifications of proliferating cell nuclear antigen: acetylation, not phosphorylation, plays an important role in the regulation of its function. J Biol Chem. 2004;279(19):20194–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Hoelz DJ, Arnold RJ, Dobrolecki LE, Abdel-Aziz W, Loehrer AP, Novotny MV, et al. The discovery of labile methyl esters on proliferating cell nuclear antigen by MS/MS. Proteomics. 2006;6(17):4808–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Pan Y, Zhang Y, Chen L, Liu Y, Feng Y, Yan J. The critical role of Rab31 in cell proliferation and apoptosis in cancer progression. Mol Neurobiol. 2015. [Epub ahead of print] PMID: 26245486Google Scholar
  11. 11.
    Ng IO, Lai EC, Fan ST, Ng M, Chan AS, So MK. Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma. Cancer. 1994;73(9):2268–74.CrossRefPubMedGoogle Scholar
  12. 12.
    Cao J, Hu X, Xie M, Sun J, Cheng H. Expression of proliferating cell nuclear antigen and alpha-fetoprotein in hepatocellular carcinoma and its clinical significance. Pract J Cancer. 1998;13(2):105–7.Google Scholar
  13. 13.
    Zhang Z, Wu Q, Hua Z, Zhou Z, Jia Z, Wang H. The expression of PCNA CD44v6 in human hepatic carcinoma and its clinical significance. Hainan Med J. 2000;11(6):8–11.Google Scholar
  14. 14.
    Claudio PP, Russo G, Kumar CA, Minimo C, Farina A, Tutton S, et al. pRb2/p130, vascular endothelial growth factor, p27(KIP1), and proliferating cell nuclear antigen expression in hepatocellular carcinoma: their clinical significance. Clin Cancer Res. 2004;10(10):3509–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Qin HX, Nan KJ, Yang G, Jing Z, Ruan ZP, Li CL, et al. Expression and clinical significance of TAp73alpha, p53, PCNA and apoptosis in hepatocellular carcinoma. World J Gastroenterol. 2005;11(18):2709–13.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhao Z, Zhan Y, Ni Y, Zhang M, Wang C. Prognosis and the expression of survivin protein and proliferating cell nuclear antigen (PCNA) in hepatocellular carcinoma. Shenzhen J Int Trad Chin West Med. 2007;17(6):355–7.Google Scholar
  17. 17.
    Hu TH, Wang CC, Huang CC, Chen CL, Hung CH, Chen CH, et al. Down-regulation of tumor suppressor gene PTEN, overexpression of p53, plus high proliferating cell nuclear antigen index predict poor patient outcome of hepatocellular carcinoma after resection. Oncol Rep. 2007;18(6):1417–26.PubMedGoogle Scholar
  18. 18.
    Gao F, Yang J, Liu B, Ma F, Geng Y, Li J. Expressions of PCNA and Hpa and their correlations with prognosis of patients with hepatocellular carcinoma. Hebei Med J. 2013;35(16):2410–2.Google Scholar
  19. 19.
    Qiu W, Wang G, Sun X, Ye J, Wei F, Shi X, et al. The involvement of cell surface nucleolin in the initiation of CCR6 signaling in human hepatocellular carcinoma. Med Oncol. 2015;32(3):75.CrossRefPubMedGoogle Scholar
  20. 20.
    Li X, Liu X, Cui D, Wu X, Qian R. Clinical significance of nucleostemin and proliferating cell nuclear antigen protein expression in non-small cell lung cancer. J BUON. 2015;20(4):1088–93.PubMedGoogle Scholar
  21. 21.
    Poosarla C, Ramesh M, Ramesh K, Gudiseva S, Bala S, Sundar M. Proliferating cell nuclear antigen in premalignancy and oral squamous cell carcinoma. J Clin Diagn Res. 2015;9(6):ZC39–41.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Lan HA, Zain RB, Saitoh M, Muramatsu Y, Shrestha P, Mori M. Proliferating cell nuclear antigen and p53 in epithelial dysplasia and squamous cell carcinoma of oral mucosa—a marker for poor tumour differentiation, increasing nuclear atypia and invasiveness. Anticancer Res. 1996;16:3059–65.PubMedGoogle Scholar
  23. 23.
    Lv Q, Zhang J, Yi Y, Huang Y, Wang Y, Wang Y, et al. Proliferating cell nuclear antigen has an association with prognosis and risks factors of cancer patients: a systematic review. Mol Neurobiol. 2015. [Epub ahead of print] PMID: 26558632Google Scholar
  24. 24.
    Li J, Li H, Liu J, Feng B, Feng M, Lv B, et al. The clinical implications of human telomerase reverse transcriptase expression in grade and prognosis of gliomas: a systematic review and meta-analysis. Mol Neurobiol. 2015. [Epub ahead of print].Google Scholar
  25. 25.
    Bowman GD, Goedken ER, Kazmirski SL, O’Donnell M, Kuriyan J. DNA polymerase clamp loaders and DNA recognition. FEBS Lett. 2005;579:863–7.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shuangshuang Ma
    • 1
    • 2
  • Junsheng Yang
    • 3
  • Jinpeng Li
    • 1
  • Jinlong Song
    • 1
  1. 1.Department of Surgical Oncology (Interventional Therapy)Shandong Cancer Hospital and Institute, Shandong Academy of Medical SciencesJinanChina
  2. 2.School of Medicine and Life SciencesUniversity of Jinan, Shandong Academy of Medical SciencesJinanChina
  3. 3.Department of OncologyZaozhuang Municipal HospitalZaozhuangChina

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