Skip to main content

Advertisement

SpringerLink
Log in

Clinical application of protein induced by vitamin K antagonist-II as a biomarker in hepatocellular carcinoma

  • Review
  • Published:
Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Early diagnosis improves the prognosis. Protein induced by vitamin K antagonist-II (PIVKA-II) is an effective serum biomarker for HCC diagnosis and prognosis. Combined with another serum biomarker α-fetoprotein (AFP), the sensitivity and specificity of HCC diagnosis can be improved to a maximum of 94 and 98.5 %, respectively. PIVKA-II alone or in combination with AFP and/or AFP-L3 was effective in predicting the treatment response and clinical outcome of curative hepatic resection, chemotherapy, targeted therapy, radiotherapy, and liver transplantation. Japanese clinical guidelines recommend the combined use of PIVKA-II and AFP for the diagnosis of HCC, management of high-risk population, and prognosis of anticancer treatment. Further, PIVKA-II as a functional target promoted HCC cell proliferation, invasion, and metastasis by activating c-Met and other signal transduction pathways. Inhibition of PIVKA-II may provide a selective and effective therapy for HCC.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hemker HC, Veltkamp JJ, Hensen A, Loeliger EA. Nature of prothrombin biosynthesis: preprothrombinaemia in vitamin K-deficiency. Nature. 1963;200:589–90.

    Article  CAS  PubMed  Google Scholar 

  2. Stenflo J, Fernlund P, Egan W, Roepstorff P, Vitamin K. Dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A. 1974;71(7):2730–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liebman HA, Furie BC, Tong MJ, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. 1984;310(22):1427–31.

    Article  CAS  PubMed  Google Scholar 

  4. Ganrot PO, Nilehn JE. Plasma prothrombin during treatment with Dicumarol. II. Demonstration of an abnormal prothrombin fraction. Scand J Clin Lab Invest. 1968;22(1):23–8.

    Article  CAS  PubMed  Google Scholar 

  5. Nilehn JE, Ganrot PO. Plasma prothrombin during treatment with Dicumarol. I. Immunochemical determination of its concentration in plasma. Scand J Clin Lab Invest. 1968;22(1):17–22.

    Article  CAS  PubMed  Google Scholar 

  6. Stenflo J, Vitamin K. And the biosynthesis of prothrombin. II. Structural comparison of normal and dicoumarol-induced bovine prothrombin. J Biol Chem. 1972;247(24):8167–75.

    CAS  PubMed  Google Scholar 

  7. Stenflo J, Ganrot PO. Vitamin K and the biosynthesis of prothrombin. I. Identification and purification of a dicoumarol-induced abnormal prothrombin from bovine plasma. J Biol Chem. 1972;247(24):8160–6.

    CAS  PubMed  Google Scholar 

  8. Fernlund P, Stenflo J, Roepstorff P, Thomsen J. Vitamin K and the biosynthesis of prothrombin. V. Gamma-carboxyglutamic acids, the vitamin K-dependent structures in prothrombin. J Biol Chem 1975; 250(15): 6125–6133.

  9. Morris HR, Dell A. Mass-spectrometric identification and sequence location of the ten residues of the new amino acid (gamma-carboxyglutamic acid) in the N-terminal region of prothrombin. The Biochemical journal. 1976;153(3):663–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pozzi N, Chen Z, Gohara DW, Niu W, Heyduk T, Di Cera E. Crystal structure of prothrombin reveals conformational flexibility and mechanism of activation. J Biol Chem. 2013;288(31):22734–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Liebman HA. Isolation and characterization of a hepatoma-associated abnormal (des-gamma-carboxy)prothrombin. Cancer Res. 1989;49(23):6493–7.

    CAS  PubMed  Google Scholar 

  12. Naraki T, Kohno N, Saito H, et al. Gamma-carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin. Biochim Biophys Acta. 2002;1586(3):287–98.

    Article  CAS  PubMed  Google Scholar 

  13. Brown MA, Stenberg LM, Persson U, Stenflo J. Identification and purification of vitamin K-dependent proteins and peptides with monoclonal antibodies specific for gamma-carboxyglutamyl (Gla) residues. J Biol Chem. 2000;275(26):19795–802.

    Article  CAS  PubMed  Google Scholar 

  14. Ratcliffe JV, Furie B, Furie BC. The importance of specific gamma-carboxyglutamic acid residues in prothrombin. Evaluation by site-specific mutagenesis. J Biol Chem. 1993;268(32):24339–45.

    CAS  PubMed  Google Scholar 

  15. Soriano-Garcia M, Padmanabhan K, de Vos AM, Tulinsky A. The Ca2+ ion and membrane binding structure of the Gla domain of Ca-prothrombin fragment 1. Biochemistry. 1992;31(9):2554–66.

    Article  CAS  PubMed  Google Scholar 

  16. Kudo M, Takamine Y, Nakamura K, et al. Des-gamma-carboxy prothrombin (PIVKA-II) and alpha-fetoprotein-producing IIc-type early gastric cancer. Am J Gastroenterol. 1992;87(12):1859–62.

    CAS  PubMed  Google Scholar 

  17. Hyodo T, Kawamoto R. Double cancer of the stomach, one AFP-producing tumor. J Gastroenterol. 1996;31(6):851–4.

    Article  CAS  PubMed  Google Scholar 

  18. Ando E, Oriishi T, Toyonaga A, et al. Alpha-fetoprotein- and des-gamma-carboxy prothrombin-producing advanced gastric cancer. European journal of gastroenterology & hepatology. 2002;14(6):687–91.

    Article  CAS  Google Scholar 

  19. Takahashi Y, Inoue T. Des-gamma carboxy prothrombin (PIVKA-II) and alpha-fetoprotein producing gastric cancer with multiple liver metastases. Pathol Int. 2003;53(4):236–40.

    Article  PubMed  Google Scholar 

  20. Takano S, Honda I, Watanabe S, et al. PIVKA-II-producing advanced gastric cancer. Int J Clin Oncol. 2004;9(4):330–3.

    Article  PubMed  Google Scholar 

  21. Takahashi Y, Endo H, Tange T, et al. Des-gamma carboxy prothrombin (PIVKA-II)- and alpha-fetoprotein (AFP)-producing gastric cancer. J Gastroenterol. 2005;40(4):432–3.

    Article  PubMed  Google Scholar 

  22. Kemik AS, Kemik O, Purisa S, Tuzun S. Serum des-gamma-carboxyprothrombin in patients with pancreatic head adenocarcinoma. Bratislavske lekarske listy. 2011;112(10):552–4.

    CAS  PubMed  Google Scholar 

  23. Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem. 1985;54:459–77.

    Article  CAS  PubMed  Google Scholar 

  24. Yamagata H, Nakanishi T, Furukawa M, Okuda H, Obata H. Levels of vitamin K, immunoreactive prothrombin, des-gamma-carboxy prothrombin and gamma-glutamyl carboxylase activity in hepatocellular carcinoma tissue. J Gastroenterol Hepatol. 1995;10(1):8–13.

    Article  CAS  PubMed  Google Scholar 

  25. Shah DV, Zhang P, Engelke JA, Bach AU, Suttie JW. Vitamin K-dependent carboxylase activity, prothrombin mRNA, and prothrombin production in two cultured rat hepatoma cell lines. Thromb Res. 1993;70(5):365–73.

    Article  CAS  PubMed  Google Scholar 

  26. Shah DV, Engelke JA, Suttie JW. Abnormal prothrombin in the plasma of rats carrying hepatic tumors. Blood. 1987;69(3):850–4.

    CAS  PubMed  Google Scholar 

  27. Miyakawa T, Kajiwara Y, Shirahata A, Okamoto K, Itoh H, Ohsato K, Vitamin K. Contents in liver tissue of hepatocellular carcinoma patients. Japanese journal of cancer research : Gann. 2000;91(1):68–74.

    Article  CAS  PubMed  Google Scholar 

  28. Ma M, XJ Q, GY M, et al. Vitamin K2 inhibits the growth of hepatocellular carcinoma via decrease of des-gamma-carboxy prothrombin. Chemotherapy. 2009;55(1):28–35.

    Article  CAS  PubMed  Google Scholar 

  29. Ishizuka M, Kubota K, Shimoda M, et al. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res. 2012;32(12):5415–20.

    CAS  PubMed  Google Scholar 

  30. Carr BI, Wang Z, Wang M, Wei G. Differential effects of vitamin K1 on AFP and DCP levels in patients with unresectable HCC and in HCC cell lines. Dig Dis Sci. 2011;56(6):1876–83.

    Article  CAS  PubMed  Google Scholar 

  31. Murata K, Suzuki H, Okano H, Oyamada T, Yasuda Y, Sakamoto A. Hypoxia-induced des-gamma-carboxy prothrombin production in hepatocellular carcinoma. Int J Oncol. 2010;36(1):161–70.

    CAS  PubMed  Google Scholar 

  32. Suzuki H, Murata K, Gotoh T, et al. Phenotype-dependent production of des-gamma-carboxy prothrombin in hepatocellular carcinoma. J Gastroenterol. 2011;46(10):1219–29.

    Article  CAS  PubMed  Google Scholar 

  33. Ono M, Ohta H, Ohhira M, Sekiya C, Namiki M. Measurement of immunoreactive prothrombin, des-gamma-carboxy prothrombin, and vitamin K in human liver tissues: overproduction of immunoreactive prothrombin in hepatocellular carcinoma. Am J Gastroenterol. 1990;85(9):1149–54.

    CAS  PubMed  Google Scholar 

  34. Suzuki M, Shiraha H, Fujikawa T, et al. Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma. J Biol Chem. 2005;280(8):6409–15.

    Article  CAS  PubMed  Google Scholar 

  35. Inagaki Y, Qi F, Gao J, et al. Effect of c-met inhibitor SU11274 on hepatocellular carcinoma cell growth. Bioscience trends. 2011;5(2):52–6.

    Article  CAS  PubMed  Google Scholar 

  36. Gao J, Feng X, Inagaki Y, et al. Des-gamma-carboxy prothrombin and c-met were concurrently and extensively expressed in hepatocellular carcinoma and associated with tumor recurrence. Bioscience trends. 2012;6(4):153–9.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang YS, Chu JH, Song ZY, Cui SX, Des-gamma-carboxy QXJ. Prothrombin (DCP) antagonizes the effects of gefitinib on human hepatocellular carcinoma cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2015;35(1):201–12.

    Article  CAS  Google Scholar 

  38. Morimoto Y, Nouso K, Wada N, et al. Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma. Hepatology research : the official journal of the Japan Society of Hepatology. 2014;44(14):E353–9.

    Article  Google Scholar 

  39. Yue P, Gao ZH, Xue X, et al. Des-gamma-carboxyl prothrombin induces matrix metalloproteinase activity in hepatocellular carcinoma cells by involving the ERK1/2 MAPK signalling pathway. Eur J Cancer. 2011;47(7):1115–24.

    Article  CAS  PubMed  Google Scholar 

  40. Wang SB, Cheng YN, Cui SX, et al. Des-gamma-carboxy prothrombin stimulates human vascular endothelial cell growth and migration. Clinical & experimental metastasis. 2009;26(5):469–77.

    Article  CAS  Google Scholar 

  41. Matsubara M, Shiraha H, Kataoka J, et al. Des-gamma-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27(10):1602–8.

    Article  CAS  PubMed  Google Scholar 

  42. Singal A, Volk ML, Waljee A, et al. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37–47.

    Article  CAS  PubMed  Google Scholar 

  43. Bertino G, Ardiri AM, Boemi PM, et al. A study about mechanisms of des-gamma-carboxy prothrombin's production in hepatocellular carcinoma. Panminerva Med. 2008;50(3):221–6.

    CAS  PubMed  Google Scholar 

  44. Carr BI, Kanke F, Wise M, Satomura S. Clinical evaluation of Lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 2007;52(3):776–82.

    Article  CAS  PubMed  Google Scholar 

  45. Zhu R, Yang J, Xu L, et al. Diagnostic performance of Des-gamma-carboxy prothrombin for hepatocellular carcinoma: a meta-analysis. Gastroenterol Res Pract. 2014;2014:529314.

    PubMed  PubMed Central  Google Scholar 

  46. Tsuchiya N, Sawada Y, Endo I, Saito K, Uemura Y, Nakatsura T. Biomarkers for the early diagnosis of hepatocellular carcinoma. World journal of gastroenterology : WJG. 2015;21(37):10573–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kang KH, Kim JH, Kang SH, et al. The influence of alcoholic liver disease on serum PIVKA-II levels in patients without hepatocellular carcinoma. Gut and liver. 2015;9(2):224–30.

    Article  CAS  PubMed  Google Scholar 

  48. Toyoda H, Kumada T, Osaki Y, Tada T, Kaneoka Y, Maeda A. Novel method to measure serum levels of des-gamma-carboxy prothrombin for hepatocellular carcinoma in patients taking warfarin: a preliminary report. Cancer Sci. 2012;103(5):921–5.

    Article  CAS  PubMed  Google Scholar 

  49. Tanaka T, Taniguchi T, Sannomiya K, et al. Novel des-gamma-carboxy prothrombin in serum for the diagnosis of hepatocellular carcinoma. J Gastroenterol Hepatol. 2013;28(8):1348–55.

    Article  CAS  PubMed  Google Scholar 

  50. Hu B, Tian X, Sun J, Meng X. Evaluation of individual and combined applications of serum biomarkers for diagnosis of hepatocellular carcinoma: a meta-analysis. Int J Mol Sci. 2013;14(12):23559–80.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Huang TS, Shyu YC, Turner R, Chen HY, Chen PJ. Diagnostic performance of alpha-fetoprotein, Lens culinaris agglutinin-reactive alpha-fetoprotein, des-gamma carboxyprothrombin, and glypican-3 for the detection of hepatocellular carcinoma: a systematic review and meta-analysis protocol. Systematic reviews. 2013;2:37.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhang K, Song P, Gao J, Li G, Zhao X, Zhang S. Perspectives on a combined test of multi serum biomarkers in China: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Drug discoveries & therapeutics. 2014;8(3):102–9.

    Article  Google Scholar 

  53. Meguro M, Mizuguchi T, Nishidate T, et al. Prognostic roles of preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin in hepatocellular carcinoma patients. World journal of gastroenterology : WJG. 2015;21(16):4933–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Song P, Feng X, Inagaki Y, et al. Clinical utility of simultaneous measurement of alpha-fetoprotein and des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinoma in China: a multi-center case-controlled study of 1,153 subjects. Bioscience trends. 2014;8(5):266–73.

    Article  CAS  PubMed  Google Scholar 

  55. Ertle JM, Heider D, Wichert M, et al. A combination of alpha-fetoprotein and des-gamma-carboxy prothrombin is superior in detection of hepatocellular carcinoma. Digestion. 2013;87(2):121–31.

    Article  CAS  PubMed  Google Scholar 

  56. Yoon YJ, Han KH, Kim DY. Role of serum prothrombin induced by vitamin K absence or antagonist-II in the early detection of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Scand J Gastroenterol. 2009;44(7):861–6.

    Article  CAS  PubMed  Google Scholar 

  57. Ji J, Wang H, Li Y, et al. Diagnostic evaluation of Des-gamma-carboxy prothrombin versus alpha-fetoprotein for hepatitis B virus-related hepatocellular carcinoma in China: a large-scale, multicentre study. PLoS One. 2016;11(4):e0153227.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chon YE, Choi GH, Lee MH, et al. Combined measurement of preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin predicts recurrence after curative resection in patients with hepatitis-B-related hepatocellular carcinoma. Int J Cancer. 2012;131(10):2332–41.

    Article  CAS  PubMed  Google Scholar 

  59. Park H, Park JY. Clinical significance of AFP and PIVKA-II responses for monitoring treatment outcomes and predicting prognosis in patients with hepatocellular carcinoma. Biomed Res Int. 2013;2013:310427.

    PubMed  PubMed Central  Google Scholar 

  60. Saito M, Seo Y, Yano Y, Miki A, Yoshida M, Azuma T. A high value of serum des-gamma-carboxy prothrombin before hepatocellular carcinoma treatment can be associated with long-term liver dysfunction after treatment. J Gastroenterol. 2012;47(10):1134–42.

    Article  CAS  PubMed  Google Scholar 

  61. Hiraoka A, Ishimaru Y, Kawasaki H, et al. Tumor markers AFP, AFP-L3, and DCP in hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Oncology. 2015;89(3):167–74.

    Article  CAS  PubMed  Google Scholar 

  62. Arai T, Kobayashi A, Ohya A, et al. Assessment of treatment outcomes based on tumor marker trends in patients with recurrent hepatocellular carcinoma undergoing trans-catheter arterial chemo-embolization. Int J Clin Oncol. 2014;19(5):871–9.

    Article  CAS  PubMed  Google Scholar 

  63. Saeki I, Yamasaki T, Tanabe N, et al. A new therapeutic assessment score for advanced hepatocellular carcinoma patients receiving hepatic arterial infusion chemotherapy. PLoS One. 2015;10(5):e0126649.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Miyaki D, Kawaoka T, Aikata H, et al. Evaluation of early response to hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma using the combination of response evaluation criteria in solid tumors and tumor markers. J Gastroenterol Hepatol. 2015;30(4):726–32.

    Article  CAS  PubMed  Google Scholar 

  65. Yamamoto K, Imamura H, Matsuyama Y, et al. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC. J Gastroenterol. 2010;45(12):1272–82.

    Article  CAS  PubMed  Google Scholar 

  66. Wang BL, Tan QW, Gao XH, Wu J, Guo W. Elevated PIVKA-II is associated with early recurrence and poor prognosis in BCLC 0-a hepatocellular carcinomas. Asian Pacific journal of cancer prevention : APJCP. 2014;15(16):6673–8.

    Article  PubMed  Google Scholar 

  67. Toyoda H, Kumada T, Tada T, et al. Prognostic significance of a combination of pre- and post-treatment tumor markers for hepatocellular carcinoma curatively treated with hepatectomy. J Hepatol. 2012;57(6):1251–7.

    Article  CAS  PubMed  Google Scholar 

  68. Nakagawa S, Hayashi H, Nitta H, et al. Scoring system based on tumor markers and Child-Pugh classification for HCC patients who underwent liver resection. Anticancer Res. 2015;35(4):2157–63.

    CAS  PubMed  Google Scholar 

  69. Okamura Y, Ashida R, Ito T, Sugiura T, Mori K, Uesaka K. The tumor marker score is an independent predictor of survival in patients with recurrent hepatocellular carcinoma. Surgery today 2014.

  70. Asaoka Y, Tateishi R, Nakagomi R, et al. Frequency of and predictive factors for vascular invasion after radiofrequency ablation for hepatocellular carcinoma. PLoS One. 2014;9(11):e111662.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lee S, Rhim H, Kim YS, Kang TW, Song KD. Postablation Des-gamma-carboxy prothrombin level predicts prognosis in hepatitis B-related hepatocellular carcinoma. Liver international : official journal of the International Association for the Study of the Liver. 2015. doi:10.1111/liv.12991.

    Google Scholar 

  72. Shindoh J, Sugawara Y, Nagata R, et al. Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma. Transplant international : official journal of the European Society for Organ Transplantation. 2014;27(4):391–8.

    Article  CAS  Google Scholar 

  73. Iguchi T, Shirabe K, Aishima S, et al. New pathologic stratification of microvascular invasion in hepatocellular carcinoma: predicting prognosis after living-donor liver transplantation. Transplantation. 2015;99(6):1236–42.

    Article  CAS  PubMed  Google Scholar 

  74. Park H, Kim SU, Park JY, et al. Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma. Liver international : official journal of the International Association for the Study of the Liver. 2014;34(2):313–21.

    Article  CAS  Google Scholar 

  75. Kumada T, Toyoda H, Kiriyama S, et al. Predictive value of tumor markers for hepatocarcinogenesis in patients with hepatitis C virus. J Gastroenterol. 2011;46(4):536–44.

    Article  CAS  PubMed  Google Scholar 

  76. Omata M, Lesmana LA, Tateishi R, et al. Asian Pacific Association for the Study of the liver consensus recommendations on hepatocellular carcinoma. Hepatol Int. 2010;4(2):439–74.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Kokudo N, Hasegawa K, Akahane M, et al. Evidence-based clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines). Hepatology research : the official journal of the Japan Society of Hepatology 2015; 45(2).

  78. Kumar A, Acharya SK, Singh SP, et al. The Indian National Association for study of the liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the Puri recommendations. Journal of clinical and experimental hepatology. 2014;4(Suppl 3):S3–S26.

    Article  PubMed  PubMed Central  Google Scholar 

  79. European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.

    Article  Google Scholar 

  80. Bruix J, Sherman M. American Association for the Study of liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (Nos. 81472284, 81172020, and 81372262), Program for Excellent Young Scholars of SMMU, and Charitable Project on Scientific Research of Shanghai.

Author information

Authors and Affiliations

  1. Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China

    Hao Xing, Shuyang Dai, Jianyong Yuan, Wenfeng Lu, Zhouchong Wang, Jun Han & Tian Yang

  2. Department of Clinical Laboratory, Peking University First Hospital, Beijing, China

    Cunling Yan

  3. Department of Clinical Laboratory, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

    Liming Cheng

  4. The Second Hospital of Nanjing, Affiliated to Medical School of Southeast University, Nanjing, China

    Nianyue Wang

  5. Medical Scientific Affairs, Abbott Diagnostics, Shanghai, 200003, China

    Yijie Zheng

Authors
  1. Hao Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cunling Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liming Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nianyue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuyang Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianyong Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenfeng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhouchong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jun Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yijie Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tian Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yijie Zheng or Tian Yang.

Ethics declarations

Conflicts of interest

Yijie Zheng is an employee of Abbott Diagnostics. There are no other conflicts of interest.

Additional information

Key points

1. The basic information including the structure and the discovery process about protein induced by vitamin K antagonist-II (PIVKA-II) are introduced and discussed.

2. PIVKA-II is increased in HCC patients with approving diagnosis efficiency. The combination of PIVKA-II and AFP is recommended for early scanning of liver cancer in high risk population. The potential clinical values of PIVKA-II are worthy of expectation. PIVKA-II shows a promising future in both prognostic prediction and tumor screening.

3. PIVKA-II as a drug target promoted HCC cell proliferation, invasion, and metastasis by activating c-Met and other signal transduction pathways. Inhibition of PIVKA-II may provide a selective and effective therapy for HCC.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xing, H., Yan, C., Cheng, L. et al. Clinical application of protein induced by vitamin K antagonist-II as a biomarker in hepatocellular carcinoma. Tumor Biol. 37, 15447–15456 (2016). https://doi.org/10.1007/s13277-016-5443-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5443-x

Keywords

Search

Navigation