Archives of Virology

, Volume 162, Issue 10, pp 2937–2947 | Cite as

Modulation of Wnt signaling pathway by hepatitis B virus

  • Muhammad Daud
  • Muhammad Adeel Rana
  • Tayyab Husnain
  • Bushra Ijaz


Hepatitis B virus (HBV) has a global distribution and is one of the leading causes of hepatocellular carcinoma. The precise mechanism of pathogenicity of HBV-associated hepatocellular carcinoma (HCC) is not yet fully understood. Viral-related proteins are known to take control of several cellular pathways like Wnt/β-catenin, TGF-β, Raf/MAPK and ROS for the virus’s own replication. This affects cellular persistence, multiplication, migration, alteration and genomic instability. The Wnt/FZD/β-catenin signaling pathway plays a significant role in the pathology and physiology of the liver and has been identified as a main factor in HCC development. The role of β-catenin is linked mainly to the canonical pathway of the signaling system. Progression of liver diseases is known to be accompanied by disturbances in β-catenin expression (mainly overexpression), with its cytoplasmic or nuclear translocation. In recent years, studies have documented that the HBV X protein and hepatitis B surface antigen (HBsAg) can act as pathogenic factors that are involved in the modulation and induction of canonical Wnt signaling pathway. In the present review we explore the interaction of HBV genome products with components of the Wnt/β–catenin signaling pathway that results in the enhancement of the pathway and leads to hepatocarcinogenesis.



We are thankful to Mr. Seth Fortmann (University of Alabama, School of Medicine, USA) for editing the manuscript and Mr. Muhammad Shehzad Latif (Floriculture lab, Centre of Excellence in Molecular Biology, University of the Punjab) for helping us with the figures.

Compliance with ethical standards


The study is not funded by any company or funding agency.

Conflict of interest

All four authors have no institutional or financial competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Tong S, Revill P (2016) Overview of hepatitis B viral replication and genetic variability. J Hepatol 64(1):S4–S16CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schinazi RF, Asselah T (2017) From HCV To HBV Cure. Liver Int 37(S1):73–80CrossRefPubMedGoogle Scholar
  3. 3.
    Liang TJ (2009) Hepatitis B: the virus and disease. Hepatology 49(S5):S13–S21CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Milich D, Liang TJ (2003) Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38(5):1075–1086CrossRefPubMedGoogle Scholar
  5. 5.
    Han Y et al (2013) Regulation of B7-H1 expression on peripheral monocytes and IFN-γ secretion in T lymphocytes by HBeAg. Cell Immunol 283(1):25–30CrossRefPubMedGoogle Scholar
  6. 6.
    Chen M et al (2005) Immune tolerance split between hepatitis B virus precore and core proteins. J Virol 79(5):3016–3027CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Xie K-L et al (2014) MicroRNAs associated with HBV infection and HBV-related HCC. Theranostics 4(12):1176CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Miller RH, Robinson WS (1986) Common evolutionary origin of hepatitis B virus and retroviruses. Proc Natl Acad Sci 83(8):2531–2535CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Murakami S (2001) Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol 36(10):651–660CrossRefPubMedGoogle Scholar
  10. 10.
    Feitelson MA, Duan L-X (1997) Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 150(4):1141PubMedPubMedCentralGoogle Scholar
  11. 11.
    Li J et al (2016) Unusual features of sodium taurocholate cotransporting polypeptide as a hepatitis B virus receptor. J Virol 90(18):8302–8313CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Urban S et al (2010) The replication cycle of hepatitis B virus. J Hepatol 52(2):282–284CrossRefPubMedGoogle Scholar
  13. 13.
    Rajbhandari R, Chung RT (2016) Treatment of hepatitis B: a concise review. Clin Transl Gastroenterol 7(9):e190CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bhattacharya D, Thio CL (2010) Review of hepatitis B therapeutics. Clin Infect Dis 51(10):1201–1208CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Grimm D, Thimme R, Blum HE (2011) HBV life cycle and novel drug targets. Hepatol Int 5(2):644–653CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen GF, Wang C, Lau G (2017) Treatment of chronic hepatitis B infection-2017. Liver Int 37(S1):59–66CrossRefPubMedGoogle Scholar
  17. 17.
    Bejsovec A (2006) Flying at the head of the pack: Wnt biology in Drosophila. Oncogene 25(57):7442–7449CrossRefPubMedGoogle Scholar
  18. 18.
    Brunt LH et al (2017) Wnt Signalling controls the response to mechanical loading during zebrafish joint development. 115105 (bioRxiv2017)Google Scholar
  19. 19.
    Clevers H (2006) Wnt/β-catenin signaling in development and disease. Cell 127(3):469–480CrossRefPubMedGoogle Scholar
  20. 20.
    Kumawat K, Gosens R (2016) WNT-5A: signaling and functions in health and disease. Cell Mol Life Sci 73(3):567–587CrossRefPubMedGoogle Scholar
  21. 21.
    Ockeloen CW et al (2016) Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genet Med 18(11):1158–1162CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mulligan KA, Cheyette BN (2016) Neurodevelopmental perspectives on Wnt signaling in psychiatry. Mol Neuropsychiatry 2(4):219–246CrossRefGoogle Scholar
  23. 23.
    Skronska-Wasek W et al (2017) Reduced Frizzled receptor 4 expression prevents WNT/β-catenin-driven alveolar lung repair in COPD. Am J Respir Crit Care Med. doi: 10.1164/rccm.201605-0904OC PubMedGoogle Scholar
  24. 24.
    Takahashi H et al (2017) Possible role of nuclear β-catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer. Histol. doi: 10.1111/his.13227 Google Scholar
  25. 25.
    MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115(21):3977–3978CrossRefPubMedGoogle Scholar
  27. 27.
    Hart M et al (1999) The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Curr Biol 9(4):207–211CrossRefPubMedGoogle Scholar
  28. 28.
    Kimelman D, Xu W (2006) β-Catenin destruction complex: insights and questions from a structural perspective. Oncogene 25(57):7482–7491CrossRefPubMedGoogle Scholar
  29. 29.
    Liu C et al (1999) β-Trcp couples β-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc Natl Acad Sci 96(11):6273–6278CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Liu C et al (2002) Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108(6):837–847CrossRefPubMedGoogle Scholar
  31. 31.
    Price MA (2006) CKI, there’s more than one: casein kinase I family members in Wnt and Hedgehog signaling. Genes Dev 20(4):399–410CrossRefPubMedGoogle Scholar
  32. 32.
    Ozawa M, Baribault H, Kemler R (1989) The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 8(6):1711PubMedPubMedCentralGoogle Scholar
  33. 33.
    Pez F et al (2013) Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol 59(5):1107–1117CrossRefPubMedGoogle Scholar
  34. 34.
    Laurent-Puig P, Zucman-Rossi J (2006) Genetics of hepatocellular tumors. Oncogene 25(27):3778–3786CrossRefPubMedGoogle Scholar
  35. 35.
    Arbuthnot P, Kew M (2001) Hepatitis B virus and hepatocellular carcinoma. Int J Exp Pathol 82(2):77–100CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Levrero M, Zucman-Rossi J (2016) Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 64(1):S84–S101CrossRefPubMedGoogle Scholar
  37. 37.
    Huang H et al (1999) β-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 155(6):1795–1801CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hsu H-C et al (2000) β-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 157(3):763–770CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wong CM, Fan ST, Ng IO (2001) β-catenin mutation and overexpression in hepatocellular carcinoma. Cancer 92(1):136–145CrossRefPubMedGoogle Scholar
  40. 40.
    Zucman-Rossi J et al (2007) Differential effects of inactivated Axin1 and activated β-catenin mutations in human hepatocellular carcinomas. Oncogene 26(5):774–780CrossRefPubMedGoogle Scholar
  41. 41.
    Cieply B et al (2009) Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology 49(3):821–831CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Austinat M et al (2008) Correlation between beta-catenin mutations and expression of Wnt-signaling target genes in hepatocellular carcinoma. Mol Cancer 7(1):21CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tornesello ML et al (2013) Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics 102(2):74–83CrossRefPubMedGoogle Scholar
  44. 44.
    Amit S et al (2002) Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 16(9):1066–1076CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Yost C et al (1996) The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev 10(12):1443–1454CrossRefPubMedGoogle Scholar
  46. 46.
    Park JY et al (2005) Mutations of β-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis. Liver Int 25(1):70–76CrossRefPubMedGoogle Scholar
  47. 47.
    Jain S et al (2011) Methylation of the CpG sites only on the sense strand of the APC gene is specific for hepatocellular carcinoma. PLoS One 6(11):e26799CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee H-H et al (2009) Wnt-1 protein as a prognostic biomarker for hepatitis B-related and hepatitis C-related hepatocellular carcinoma after surgery. Cancer Epidemiol Biomark Prevent 18(5):1562–1569CrossRefGoogle Scholar
  49. 49.
    Cha MY et al (2004) Hepatitis B virus X protein is essential for the activation of Wnt/β-catenin signaling in hepatoma cells. Hepatology 39(6):1683–1693CrossRefPubMedGoogle Scholar
  50. 50.
    Kim M et al (2008) Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells. J Hepatol 48(5):780–791CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lin X et al (2013) Differential expression of Wnt pathway genes in sporadic hepatocellular carcinomas infected with hepatitis B virus identified with OligoGE arrays. Hepatitis Mon 13(1):e6192Google Scholar
  52. 52.
    Tamori A et al (2005) Alteration of gene expression in human hepatocellular carcinoma with integrated hepatitis B virus DNA. Clin Cancer Res 11(16):5821–5826CrossRefPubMedGoogle Scholar
  53. 53.
    Boyault S et al (2007) Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45(1):42–52CrossRefPubMedGoogle Scholar
  54. 54.
    Park N, Song I, Chung Y (2006) Chronic hepatitis B in hepatocarcinogenesis. Postgrad Med J 82(970):507–515CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Lee J-O et al (2005) Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 24(44):6617–6625CrossRefPubMedGoogle Scholar
  56. 56.
    Nelson WJ, Nusse R (2004) Convergence of Wnt, β-catenin, and cadherin pathways. Science 303(5663):1483–1487CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lara-Pezzi E et al (2001) The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene 20(26):3323–3331CrossRefPubMedGoogle Scholar
  58. 58.
    Xie Q et al (2014) Epigenetic silencing of SFRP1 and SFRP5 by hepatitis B virus X protein enhances hepatoma cell tumorigenicity through Wnt signaling pathway. Int J Cancer 135(3):635–646CrossRefPubMedGoogle Scholar
  59. 59.
    Takagi H et al (2008) Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J Gastroenterol 43(5):378–389CrossRefPubMedGoogle Scholar
  60. 60.
    Hsieh A et al (2011) Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling. Cancer Lett 300(2):162–172CrossRefPubMedGoogle Scholar
  61. 61.
    Chen Z et al (2016) HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway. Cancer Sci 107(10):1380–1389CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kuo C-Y et al (2008) HBx inhibits the growth of CCL13-HBX-stable cells via the GSK-3/-catenin cascade. Intervirology 51(2):130–136CrossRefPubMedGoogle Scholar
  63. 63.
    Peifer M, Polakis P (2000) Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 287(5458):1606–1609CrossRefPubMedGoogle Scholar
  64. 64.
    Wang Q et al (2012) A mutant of hepatitis B virus X protein (HBxΔ127) promotes cell growth through a positive feedback loop involving 5-lipoxygenase and fatty acid synthase. Neoplasia 12(2):103-IN3Google Scholar
  65. 65.
    Jung JK et al (2007) Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of β-catenin depending on the status of cellular p53. J Gen Virol 88(8):2144–2154CrossRefPubMedGoogle Scholar
  66. 66.
    Ostuni A et al (2013) The hepatitis B x antigen anti-apoptotic effector URG7 is localized to the endoplasmic reticulum membrane. FEBS Lett 587(18):3058–3062CrossRefPubMedGoogle Scholar
  67. 67.
    Lian Z et al (2006) Enhanced cell survival of Hep3B cells by the hepatitis B × antigen effector, URG11, is associated with upregulation of β-catenin. Hepatology 43(3):415–424CrossRefPubMedGoogle Scholar
  68. 68.
    Pan J et al (2007) The hepatitis B x antigen effector, URG7, blocks tumour necrosis factor α-mediated apoptosis by activation of phosphoinositol 3-kinase and β-catenin. J Gen Virol 88(12):3275–3285CrossRefPubMedGoogle Scholar
  69. 69.
    Sun Q et al (2014) Notch1 promotes hepatitis B virus X protein-induced hepatocarcinogenesis via Wnt/β-catenin pathway. Int J Oncol 45(4):1638–1648CrossRefPubMedGoogle Scholar
  70. 70.
    Tian Y et al (2017) HBx promotes cell proliferation by disturbing the cross-talk between miR-181a and PTEN. Sci Rep 7:40089CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lee S et al (2016) Hepatitis B virus X protein enhances Myc stability by inhibiting SCFSkp2 ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis. Oncogene 35(14):1857–1867CrossRefPubMedGoogle Scholar
  72. 72.
    Blumberg BS, Alter HJ (1965) A new antigen in leukemia sera. JAMA 191(7):541–546CrossRefPubMedGoogle Scholar
  73. 73.
    Tian X et al (2007) Gene-expression profiles of a hepatitis B small surface antigen-secreting cell line reveal upregulation of lymphoid enhancer-binding factor 1. J Gen Virol 88(11):2966–2976CrossRefPubMedGoogle Scholar
  74. 74.
    Tian X et al (2009) Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: regulation of lymphoid enhancer-binding factor 1. J Exp Clin Cancer Res 28(1):1CrossRefGoogle Scholar
  75. 75.
    Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Sasai N et al (2004) The neurotrophin-receptor-related protein NRH1 is essential for convergent extension movements. Nat Cell Biol 6(8):741–748CrossRefPubMedGoogle Scholar
  77. 77.
    Lu W et al (2004) Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119(1):97–108CrossRefPubMedGoogle Scholar
  78. 78.
    Lu X et al (2004) PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature 430(6995):93–98CrossRefPubMedGoogle Scholar
  79. 79.
    Nishita M et al (2006) Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol 175(4):555–562CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    He X et al (2004) LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: arrows point the way. Development 131(8):1663–1677CrossRefPubMedGoogle Scholar
  81. 81.
    Wallingford JB, Habas R (2005) The developmental biology of dishevelled: an enigmatic protein governing cell fate and cell polarity. Development 132(20):4421–4436CrossRefPubMedGoogle Scholar
  82. 82.
    Cadigan KM, Liu YI (2006) Wnt signaling: complexity at the surface. J Cell Sci 119(3):395–402CrossRefPubMedGoogle Scholar
  83. 83.
    Semenov M, He X (2003) Secreted antagonists/modulators of Wnt signaling. In: Kuhl M (ed) Wnt Signaling in Development, pp 16–25Google Scholar
  84. 84.
    Park E et al (2006) Role of PKA as a negative regulator of PCP signaling pathway during Xenopus gastrulation movements. Dev Biol 292(2):344–357CrossRefPubMedGoogle Scholar
  85. 85.
    Herbst A et al (2014) Comprehensive analysis of β-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/β-catenin signaling. BMC Genom 15(1):74CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria 2017

Authors and Affiliations

  • Muhammad Daud
    • 1
  • Muhammad Adeel Rana
    • 2
  • Tayyab Husnain
    • 1
  • Bushra Ijaz
    • 1
  1. 1.Applied and Functional Genomics Lab, Centre of Excellence in Molecular BiologyUniversity of the PunjabLahorePakistan
  2. 2.Department of MicrobiologyQuaid-i-Azam UniversityIslamabadPakistan

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