The function of HBx in HBV-induced hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is the second cause cancer death in the world. HCC is frequently diagnosed at advanced stages with intrahepatic metstasis or vascular invasion and has a poor prognosis with a high mortality rate. In the world, hepatitis B virus (HBV) caused over 50% HCC, making it the most common carcinogen after tobacco. Notably, accumulating evidence suggests HBV X gene (HBx) play an important role in tumorigenesis of HBV-related HCC. In this review, we will summarize the functions of HBx proteins in tumorigenesis and discuss their potential implications in cancer therapy.

1 Introduction

Liver cancer is the fifth most common cancer in the world1, It is estimated that every year about more than 500,000 people death for Hepatocellular carcinoma (HCC)2. hepatitis B virus (HBV) is a kind of multi-functional regulatory protein and mainly promote HCC development3. It is a kind of double link DNA virus. It’s contained four open reading frame, respectively coded 4 kinds of protein S, X, E, C4. A multifunctional protein HBx is encoded by the X gene of HBV, It has reported that HBx has multifunctional, including transcriptional activion5,6,7,8,9,10,11, epigenetic regulation12,13,14, apoptosis regulation15, DNA repair regulation16,17,18 and so on.

2 Correlation between HBx and hepatocellular carcinoma

HBx often restructured in the host cell genome19. In recent years, more and more significant advancement in the molecular mechanisms about the role of in HCC. Continuous replication in the host is an important process of HCC. In the process of chronic liver disease, the regeneration of infected hepatocytes leads to the integration of HBx into the host gene. It is an important biological process in the early stages of HCC. HBx transgenic mice are more likely to develop HCC20, and repolication of HBV will be enhance when HBx integrated into the host genome21.

3 HBx, transcriptional control

HBx was recruited to HBV replication cells in cccDNA microchromosomes to increase transcription of the nuclear cccDNA microchromosome22,23. In the absence of HBx, cccDNA-bound histones are hypo-acetylated, and cccDNA transcription was significantly less pgRNA. HBx protein can blocks the inhibitory activity on HBV transcription by binding to PRMT1 methyltransferase, the Tudor-domain protein Spindlin-1 and the SETDB1 histone methyltransferase24,25,26. HBx can reinforce HBV replication, through induction of miR-101 to downregulation of DNMT3A expression27. The genome-wide analysis of HBx chromatin recruitment in HBV replicating cells revealed a specific binding of HBx to a large number target sequences, including proteincoding genes and non-coding RNAs28.

4 Correlation between HBx and Epithelial-mesenchymal transition (EMT)

Epithelial-mesenchymal transition (EMT) plays an important role in tumor metastasis. SRC signaling is critical to the development of EMT and can promote the expression of metalloproteinases (MMPs) in a variety of ways29. HBx stimulates SRC by destroying tight junctions and promotes the development of EMT. This process is correlation with tyrosine phosphorylation of β-catenin in the Ecadherin complex30. In addition, HBx-mediated upregulation of SNAIL protein by inhibited E-cadherin expression. Recent studies have shown that HBx activates PI3K-AKT signaling pathway to stabilize SNAIL protein to promote development of HCC31.

5 HBx and cancer metabolism reprogram

Metabolic reprogramming is a symbol of cancer physiological changes. Cancer cells can mainly use glycolytic for energy metabolism. So it allows cells to use glycolytic intermediates for various macromolecule biosynthesis, in order to meet the materials of cell rapid proliferation of and energy demand. Glucose-6-phosphate dehydrogenase (G6PD) is the first rate-limiting enzyme for the pentose phosphorylation pathway, which is highly expressed in human hepatitis B and HBV-associated hepatocellular carcinoma, infected with chronic hepatitis B virus (HBV) X protein (HBx) stimulates activation of the Nrf2 activation pathway to promote G6PD expression32.

In HCC, HBx protein can directly binding with MDM2 and inhibiting its ubiquitin-directed self-degradation. This change activated the Wnt/beta-catenin pathway, so promotes the stem-like properties of OV6(+) liver CSCs33.

6 Conclusions

HBV has been regarded as the major dangerous factor for liver cancer. HCC is the most common global cancer. However, the mechanism of HBV-mediated pathogenesis still unknown. Evidence suggests that HBx plays a vital role in the development of HCC. HBx protein is involved in transcriptional regulation, signal transduction, cell cycle progression, apoptosis, and protein degradation pathway. Because HBX protein function is so diverse, so more and more research is needed to explore its unknown function. To clarify the role of HBx in the development and progression of hepatocellular carcinoma from the perspective of biology could provide a new research strategy for the future clinical treatment of liver cancer.

References

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    Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2:533–543.

    • Crossref
    • Export Citation
  • [2]

    Venook AP Papandreou C Furuse J de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 2010; 15:5–13.

    • Crossref
    • Export Citation
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    Cancer IARC. Globocan. Estimated cancer incidence mortality and prevalence worldwide in 2012. World Health Organization 2012.9.

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    Tang H. Oishi N. Kaneko S. and Murakami S. Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci 2006; 97 977–983.

    • Crossref
    • Export Citation
  • [5]

    Kew M C.Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol 2011 26:144-152.

    • Crossref
    • Export Citation
  • [6]

    Balsano C Avantaggiati M L Natoli G et al. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun 1991 176(3): 985-992.

    • Crossref
    • Export Citation
  • [7]

    Chirillo P Falco M Puri P L et al. Hepatitis B virus Px activates NF-kappa B-dependent transcription through a Rafindependent Pathway. J Virol 199670(1):641-646.

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    Choi B H Park G T Rho H M. Interaction of hepatitis B viral X protein and CCAAT/enhancer-binding protein alpha synergistically activates the hepatitis B viral enhancerΠ/pregenomic promoter. J Biol Chem 1999 274(5):2858-2865.

    • Crossref
    • Export Citation
  • [9]

    Kim H R Lee S H Jung G. The hepatitis B viral X protein activates NF-kappa B signaling pathway through the up-regulation of TBK1. FEBS Lett 2010 584(3):525-530.

    • Crossref
    • Export Citation
  • [10]

    Tanaka Y Kanai F Ichimura T et al.The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. Oncogene 2006 25(4):633-642.

    • Crossref
    • Export Citation
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    Twu J S Lai M Y Chen D S et al. Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology 1993 192(1):346-350.

    • Crossref
    • Export Citation
  • [12]

    Jung J K Park S H Jang K L.Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation. J Gen Virol 2010 91(Pt2):493-500.

    • Crossref
    • Export Citation
  • [13]

    Lee J O Kwun H J Jung J K et al.Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 2005 24(44):6617-6625.

    • Crossref
    • Export Citation
  • [14]

    Zhu Y Z Zhu R Fan J et al. Hepatitis B virus X protein induces hypermethylation of p16 (INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. J Viral Hepat 2010 17(2):98-107.

    • Crossref
    • Export Citation
  • [15]

    Arbuthnot P Capovilla A Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis DNA repair mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 2000 15(4):357-368.

    • Crossref
    • Export Citation
  • [16]

    Martin-Lluesma S Schaeffer C Robert E I et al. Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology 2008 48(5):1467-1476.

    • Crossref
    • Export Citation
  • [17]

    Lee A T Ren J Wong E T et al. The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage. J Biol Chem 2005 280(39):33525-33535.

    • Crossref
    • Export Citation
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    Becker S A Lee T H Butel J S et al.Hepatitis B virus X protein interferes with cellular DNA repair. J Virol 1998 72(1):266-272.

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    Vitvitski-Trepo L Kay A Pichoud C et al. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology 1990 12(6):1278-1283.

    • Crossref
    • Export Citation
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    Wang Y Cui F Lv Y et al. HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004 39(2):318-324.

    • Crossref
    • Export Citation
  • [21]

    Lara-Pezzi E Roche S Andrisani O M et al. The hepatitis B virus HBx protein induces adherens junction disruption in a srcdependent manner. Oncogene 2001 20(26):3323-3331.

    • Crossref
    • Export Citation
  • [22]

    Belloni L Pollicino T De Nicola F et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci U S A 2009 106:19975–19979.

    • Crossref
    • Export Citation
  • [23]

    Lucifora J Arzberger S Durantel D et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol 2011 55:996–1003.

    • Crossref
    • Export Citation
  • [24]

    Benhenda S Ducroux A Rivière L Sobhian B Ward MD Dion S et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J Virol 2013; 87:4360–4371.

    • Crossref
    • Export Citation
  • [25]

    Ducroux A Benhenda S Rivière L et al. The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B Virus and herpes simplex virus type 1. PLoS Pathog 2014 10 e1004343.

    • Crossref
    • Export Citation
  • [26]

    Rivière L Gerossier L Ducroux A Dion S Deng Q Michel ML et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. J Hepatol 2015 63:1093–1102.

    • Crossref
    • Export Citation
  • [27]

    Wei X Xiang T Ren G Tan C et al. MiR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A. Cell Signal 2013 25:439–446.

    • Crossref
    • Export Citation
  • [28]

    Guerrieri F Belloni L D’Andrea D. Genome-wide identification of direct HBx targets that control HBV replication. Gastroenterology 2015.

  • [29]

    Shih W L Kuo M L Chuang S E et al. Hepatitis B virus X protein activates a survival signaling by linking SRC to phosphatidylinositol 3-kinase. J Biol Chem 2003 278(34): 31807-31813.

    • Crossref
    • Export Citation
  • [30]

    Lara-Pezzi E Roche S Andrisani O M et al. The hepatitis B virus HBx protein induces adherens junction disruption in a srcdependent manner. Oncogene 2001 20(26):3323-3331.

    • Crossref
    • Export Citation
  • [31]

    Liu H Xu L He H et al. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein. Cancer Sci 2012 103(12):2072-2081.

    • Crossref
    • Export Citation
  • [32]

    Liu B Fang M He Z Cui D Jia S Lin X et al. Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis 2015.322.

  • [33]

    Wang C Wang MD Cheng P Huang H et al. Hepatitis B virus X protein promotes the stem-like properties of OV6(+) cancer cells in hepatocellular carcinoma. Cell Death Dis 2017. 8 e2560.

    • Crossref
    • Export Citation

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  • [1]

    Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2:533–543.

    • Crossref
    • Export Citation
  • [2]

    Venook AP Papandreou C Furuse J de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 2010; 15:5–13.

    • Crossref
    • Export Citation
  • [3]

    Cancer IARC. Globocan. Estimated cancer incidence mortality and prevalence worldwide in 2012. World Health Organization 2012.9.

  • [4]

    Tang H. Oishi N. Kaneko S. and Murakami S. Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci 2006; 97 977–983.

    • Crossref
    • Export Citation
  • [5]

    Kew M C.Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol 2011 26:144-152.

    • Crossref
    • Export Citation
  • [6]

    Balsano C Avantaggiati M L Natoli G et al. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun 1991 176(3): 985-992.

    • Crossref
    • Export Citation
  • [7]

    Chirillo P Falco M Puri P L et al. Hepatitis B virus Px activates NF-kappa B-dependent transcription through a Rafindependent Pathway. J Virol 199670(1):641-646.

  • [8]

    Choi B H Park G T Rho H M. Interaction of hepatitis B viral X protein and CCAAT/enhancer-binding protein alpha synergistically activates the hepatitis B viral enhancerΠ/pregenomic promoter. J Biol Chem 1999 274(5):2858-2865.

    • Crossref
    • Export Citation
  • [9]

    Kim H R Lee S H Jung G. The hepatitis B viral X protein activates NF-kappa B signaling pathway through the up-regulation of TBK1. FEBS Lett 2010 584(3):525-530.

    • Crossref
    • Export Citation
  • [10]

    Tanaka Y Kanai F Ichimura T et al.The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. Oncogene 2006 25(4):633-642.

    • Crossref
    • Export Citation
  • [11]

    Twu J S Lai M Y Chen D S et al. Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology 1993 192(1):346-350.

    • Crossref
    • Export Citation
  • [12]

    Jung J K Park S H Jang K L.Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation. J Gen Virol 2010 91(Pt2):493-500.

    • Crossref
    • Export Citation
  • [13]

    Lee J O Kwun H J Jung J K et al.Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 2005 24(44):6617-6625.

    • Crossref
    • Export Citation
  • [14]

    Zhu Y Z Zhu R Fan J et al. Hepatitis B virus X protein induces hypermethylation of p16 (INK4A) promoter via DNA methyltransferases in the early stage of HBV-associated hepatocarcinogenesis. J Viral Hepat 2010 17(2):98-107.

    • Crossref
    • Export Citation
  • [15]

    Arbuthnot P Capovilla A Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis DNA repair mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 2000 15(4):357-368.

    • Crossref
    • Export Citation
  • [16]

    Martin-Lluesma S Schaeffer C Robert E I et al. Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology 2008 48(5):1467-1476.

    • Crossref
    • Export Citation
  • [17]

    Lee A T Ren J Wong E T et al. The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage. J Biol Chem 2005 280(39):33525-33535.

    • Crossref
    • Export Citation
  • [18]

    Becker S A Lee T H Butel J S et al.Hepatitis B virus X protein interferes with cellular DNA repair. J Virol 1998 72(1):266-272.

  • [19]

    Vitvitski-Trepo L Kay A Pichoud C et al. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology 1990 12(6):1278-1283.

    • Crossref
    • Export Citation
  • [20]

    Wang Y Cui F Lv Y et al. HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004 39(2):318-324.

    • Crossref
    • Export Citation
  • [21]

    Lara-Pezzi E Roche S Andrisani O M et al. The hepatitis B virus HBx protein induces adherens junction disruption in a srcdependent manner. Oncogene 2001 20(26):3323-3331.

    • Crossref
    • Export Citation
  • [22]

    Belloni L Pollicino T De Nicola F et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci U S A 2009 106:19975–19979.

    • Crossref
    • Export Citation
  • [23]

    Lucifora J Arzberger S Durantel D et al. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol 2011 55:996–1003.

    • Crossref
    • Export Citation
  • [24]

    Benhenda S Ducroux A Rivière L Sobhian B Ward MD Dion S et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J Virol 2013; 87:4360–4371.

    • Crossref
    • Export Citation
  • [25]

    Ducroux A Benhenda S Rivière L et al. The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B Virus and herpes simplex virus type 1. PLoS Pathog 2014 10 e1004343.

    • Crossref
    • Export Citation
  • [26]

    Rivière L Gerossier L Ducroux A Dion S Deng Q Michel ML et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. J Hepatol 2015 63:1093–1102.

    • Crossref
    • Export Citation
  • [27]

    Wei X Xiang T Ren G Tan C et al. MiR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A. Cell Signal 2013 25:439–446.

    • Crossref
    • Export Citation
  • [28]

    Guerrieri F Belloni L D’Andrea D. Genome-wide identification of direct HBx targets that control HBV replication. Gastroenterology 2015.

  • [29]

    Shih W L Kuo M L Chuang S E et al. Hepatitis B virus X protein activates a survival signaling by linking SRC to phosphatidylinositol 3-kinase. J Biol Chem 2003 278(34): 31807-31813.

    • Crossref
    • Export Citation
  • [30]

    Lara-Pezzi E Roche S Andrisani O M et al. The hepatitis B virus HBx protein induces adherens junction disruption in a srcdependent manner. Oncogene 2001 20(26):3323-3331.

    • Crossref
    • Export Citation
  • [31]

    Liu H Xu L He H et al. Hepatitis B virus X protein promotes hepatoma cell invasion and metastasis by stabilizing Snail protein. Cancer Sci 2012 103(12):2072-2081.

    • Crossref
    • Export Citation
  • [32]

    Liu B Fang M He Z Cui D Jia S Lin X et al. Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis 2015.322.

  • [33]

    Wang C Wang MD Cheng P Huang H et al. Hepatitis B virus X protein promotes the stem-like properties of OV6(+) cancer cells in hepatocellular carcinoma. Cell Death Dis 2017. 8 e2560.

    • Crossref
    • Export Citation
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