Advertisement

Tumor Biology

, Volume 37, Issue 4, pp 5561–5568 | Cite as

Abnormality of Wnt3a expression as novel specific biomarker for diagnosis and differentiation of hepatocellular carcinoma

  • Liuhong Pan
  • Min Yao
  • Wenjie Zheng
  • Juanjuan Gu
  • Xuli Yang
  • Liwei Qiu
  • Yin Cai
  • Wei Wu
  • Dengfu Yao
Original Article

Abstract

The member 3a of Wingless-type MMTV integration site family (Wnt3a) as an oncogene is overexpressed in many kinds of tumors with a worse outcome. However, the mechanism and alteration of Wnt3a expression in hepatocellular carcinoma (HCC) have not been clarified. In this study, the levels of Wnt3a expression were investigated in 80 HCC tissues or sera of 186 patients with chronic liver diseases. The incidence of hepatic Wnt3a expression in HCC tissues was 96.25 % and significantly higher (χ 2 = 48.818, P < 0.001) than that in their surrounding tissues (46.25 %). The higher level (>800 ng/L) of circulating Wnt3a expression was found in 92.5 % HCC patients and significantly related (P < 0.05) to alpha-fetoprotein (AFP) level, liver cirrhosis, hepatitis B virus infection, poor differentiation, tumor node metastasis, and extra-hepatic metastasis. The level of Wnt3a expression in HCC patients was obviously higher (P < 0.001) than that in any group of cases with benign liver diseases. The diagnostic specificity or the area under the receiver operating characteristic curve was 94.34 % or 0.994 in Wnt3a and 69.81 % or 0.710 in AFP for HCC, respectively. The present data suggested that Wnt3a expression associated with tumor progression should be a novel specific biomarker for diagnosis and differentiation of HCC.

Keywords

ELISA Hepatocellular carcinoma Immunohistochemistry Wnt3a 

Abbreviations

AFP

Alpha-fetoprotein

ELISA

Enzyme-linked immunosorbent assay

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

IHC

Immunohistochemistry

ROC

Receiver operating characteristic curve

TMA

Tissue microarray

Wnt3a

Member 3a of Wingless-type MMTV integration site family

Notes

Acknowledgments

This work was partially supported by the Grants from the National Natural Science Foundation (81200634), the Projects of Medical Science (2014-YY-028, H201102, BL2012053, PADA, and Qinglan Program), Jiangsu Province and the International S.&T. Cooperation Program (2013DFA32150) of China, and we thank T. FitzGibbon, M.D. for the comments on earlier drafts of the manuscript.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63:844–85.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Muñoz A, Chen JG, Egner PA, Marshall ML, Johnson JL, Schneider MF, et al. Predictive power of hepatitis B 1762T/1764A mutations in plasma for hepato-cellular carcinoma risk in Qidong, China. Carcinogenesis. 2011;32:860–5.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yao DF, Horie C, Horie T, Shimizu I, Meng XY, Ito S. Virological features of hepatitis C virus infection in patients with liver diseases in the inshore area of the Yangtze River. Tokushima J Exp Med. 1994;41:49–56.PubMedGoogle Scholar
  6. 6.
    Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC, Wang N, et al. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology. 2002;36:1214–20.CrossRefPubMedGoogle Scholar
  7. 7.
    Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012;62:394–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol. 2014;35:9–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Li S, Yao D, Wang L, Wu W, Qiu L, Yao M, et al. Expression characteristics of hypoxia-inducible factor-1α and its clinical values in diagnosis and prognosis of hepatocellular carcinoma. Hepat Mon. 2011;11:821–8.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Yao DF, Jiang D, Huang Z, Lu J, Tao Q, Yu Z, et al. Abnormal expression of hepatoma specific gamma-glutamyl transferase and alteration of gamma- glutamyl transferase gene methylation status in patients with hepatocellular carcinoma. Cancer. 2000;88:761–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Wu CS, Lee TY, Chou RH, Yen CJ, Huang WC, Wu CY, et al. Development of a highly sensitive glycan microarray for quantifying AFP-L3 for early prediction of hepatitis B virus-related hepatocellular carcinoma. PLoS One. 2014;9:e99959.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yao M, Yao DF, Bian YZ, Zhang CG, Qiu LW, Wu W, et al. Oncofetal antigen glypican-3 as a promising early diagnostic marker for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2011;10:289–94.CrossRefPubMedGoogle Scholar
  13. 13.
    Yao M, Pan LH, Yao DF. Glypican-3 as a specific biomarker for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2015;14:122–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Wen Y, Han J, Chen J, Dong J, Xia Y, Liu J, et al. Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer. 2015;137:1679–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Rogacki K, Kasprzak A, Stepinski A. Alterations of Wnt/beta-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus. Pol J Pathol. 2015;66:9–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59:1107–17.CrossRefPubMedGoogle Scholar
  17. 17.
    Gao C, Xiao G, Hu J. Regulation of Wnt/beta-catenin signaling by post- translational modifications. Cell Biosci. 2014;4:13.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Willert K, Nusse R. Wnt proteins. Cold Spring Harb Perspect Biol. 2012;4:a007864.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lamb R, Ablett MP, Spence K, Landberg G, Sims AH, Clarke RB. Wnt pathway activity in breast cancer sub-types and stem-like cells. PLoS One. 2013;8:e67811.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Neth P, Ciccarella M, Egea V, Hoelters J, Jochum M, Ries C. Wnt signaling regulates the invasion capacity of human mesenchymal stem cells. Stem Cells. 2006;24:1892–903.CrossRefPubMedGoogle Scholar
  21. 21.
    Fox SA, Richards AK, Kusumah I, Perumal V, Bolitho EM, Mutsaers SE, et al. Expression profile and function of Wnt signaling mechanisms in malignant mesothelioma cells. Biochem Biophys Res Commun. 2013;440:82–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Kaur N, Chettiar S, Rathod S, Rath P, Muzumdar D, Shaikh ML, et al. Wnt3a mediated activation of Wnt/beta-catenin signaling promotes tumor progression in glioblastoma. Mol Cell Neurosci. 2013;54:44–57.CrossRefPubMedGoogle Scholar
  23. 23.
    Verras M, Brown J, Li X, Nusse R, Sun Z. Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res. 2004;64:8860–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Ministry of Health of the People’s Republic of China. Updated standards for the diagnosis and treatment of primary liver cancer. Zhonghua Gan Zang Bing Za Zhi. 2012;20:419–26.Google Scholar
  25. 25.
    OY. Management of clinical diagnosis, and antiviral therapy for HBV-related cirrhosis. Zhonghua Gan Zang Bing Za Zhi. 2014;22:327–35.Google Scholar
  26. 26.
    Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang Y, Zhang S, Wang X, Liu J, Yang L, He S, et al. Prognostic significance of FOXP1 as an oncogene in hepatocellular carcinoma. J Clin Pathol. 2012;65:528–33.CrossRefPubMedGoogle Scholar
  28. 28.
    Qian J, Yao D, Dong Z, Wu W, Qiu L, Yao N, et al. Characteristics of hepatic igf-ii expression and monitored levels of circulating igf-ii mRNA in metastasis of hepatocellular carcinoma. Am J Clin Pathol. 2010;134:799–806.CrossRefPubMedGoogle Scholar
  29. 29.
    Wei Y, Shen N, Wang Z, Yang G, Yi B, Yang N, et al. Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling. Mol Cell Biochem. 2013;381:139–44.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis. 2013;34:962–73.CrossRefPubMedGoogle Scholar
  31. 31.
    Nalesso G, Sherwood J, Bertrand J, Pap T, Ramachandran M, De Bari C, et al. WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. J Cell Biol. 2011;193:551–64.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lai JP, Oseini AM, Moser CD, Yu C, Elsawa SF, Hu C, et al. The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. Hepatology. 2010;52:1680–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yang T, Cai SY, Zhang J, Lu JH, Lin C, Zhai J, et al. Krüppel-like factor 8 is a new Wnt/beta-catenin signaling target gene and regulator in hepatocellular carcinoma. PLoS One. 2012;7:e39668.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Liu J, Ding X, Tang J, Cao Y, Hu P, Zhou F, et al. Enhancement of canonical Wnt/β-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells. PLoS One. 2011;6:e27496.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Liu J, Wang Z, Tang J, Tang R, Shan X, Zhang W, et al. Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line. Arch Virol. 2011;156:1013–23.CrossRefPubMedGoogle Scholar
  36. 36.
    Hv T, Bock CT, Velavan TP. Genetic insights on host and hepatitis B virus in liver diseases. Mutat Res Rev Mutat Res. 2014;762:65–75.CrossRefGoogle Scholar
  37. 37.
    Zhang XD, Wang Y, Ye LH. Hepatitis B virus X protein accelerates the development of hepatoma. Cancer Biol Med. 2014;11:182–90.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Suarez MI, Uribe D, Jaramillo CM, Osorio G, Perez JC, Lopez R, et al. Wnt/beta- catenin signaling pathway in hepatocellular carcinomas cases from Colombia. Ann Hepatol. 2015;14:64–74.PubMedGoogle Scholar
  39. 39.
    Yao M, Wang L, Yao Y, Gu HB, Yao DF. Biomarker-based microRNA therapeutic strategies for hepatocellular carcinoma. J Clin Transl Hepatol. 2014;2:253–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Liuhong Pan
    • 1
  • Min Yao
    • 2
  • Wenjie Zheng
    • 1
  • Juanjuan Gu
    • 3
  • Xuli Yang
    • 3
  • Liwei Qiu
    • 1
  • Yin Cai
    • 4
  • Wei Wu
    • 1
  • Dengfu Yao
    • 1
  1. 1.Research Center of Clinical MedicineAffiliated Hospital of Nantong UniversityNantongChina
  2. 2.Department of ImmunologyMedical School of Nantong UniversityNantongChina
  3. 3.Department of OncologyAffiliated Hospital of Nantong UniversityNantongChina
  4. 4.Department of PathologyAffiliated Hospital of Nantong UniversityNantongChina

Personalised recommendations