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Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma

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Abstract

Chronic hepatitis B virus (HBV) infection is a worldwide health problem. Hepatitis B virus X protein (HBx), a pleiotropic regulatory protein encoded by HBV, is necessary for the transcription of HBV covalently closed circular DNA (cccDNA) minichromosomes, and affects the epigenetic regulation of host cells. The epigenetic reprogramming of HBx on host cell genome is strongly involved in HBV-related HCC carcinogenesis. Here, we review the latest findings of the epigenetic regulation induced by HBx protein in hepatocellular carcinoma (HCC), including DNA methylation, histone modification and non-coding RNA expression. The influence of HBx on the epigenetic regulation of cccDNA is also summarized. In addition, preliminary studies of targeted drugs for epigenetic changes induced by HBx are also discussed. The exploration of epigenetic markers as potential targets will help to develop new prevention and/or treatment methods for HBx-related HCC.

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Abbreviations

HBV:

Hepatitis B virus

HBx:

Hepatitis B virus X protein

cccDNA:

Covalently closed circular DNA

HCC:

Hepatocellular carcinoma

CHB:

Chronic hepatitis B

HBV-HCC:

HBV-related HCC

ORFs:

Overlapping open reading frames

RAR-β2:

Retinoic acid receptor-beta 2

CDH1:

CpG islands in E-cadherin gene

RIZ1:

Retinoblastoma protein-interacting zinc-finger gene 1

GNA14:

Guanine nucleotide-binding protein subunit α 14

DNMTs:

DNA methyltransferases

DDB1:

Damaged DNA-binding protein 1

ncRNA:

Non-coding RNAs

SFRPs:

Secreted frizzled-related proteins

WDR5:

WD repeat domain 5 protein

lncRNA:

Long non-coding RNAs

miRNA:

MicroRNA

PIEN:

Phosphatase and tensin homolog

PI3K:

Phosphoinositide 3‑kinase

Akt:

Phosphorylated protein kinase B

EGR1:

Early growth response 1

VDAC3:

Voltage-dependent anion channel 3

CDC40:

Cell division cycle 40 homolog

FOXO1:

Forkhead box transcription factor O1

EMT:

Epithelial-mesenchymal transition

ING5:

Inhibitor of growth protein 5

STAT3:

Signal transducer and activator of transcription 3

HMGB1:

High-mobility group box 1

JNK:

C-Jun N-terminal kinase

IKKα:

Inhibitor-κB kinase-α

ZHX2:

Zinc finger homeobox 2

IGF2BP2:

Insulin-like growth factor 2 mRNA-binding protein 2

mTOR:

Mammalian target of rapamycin

MAPK:

Mitogen-activated protein kinases

ERK:

Extracellular signal-regulated kinase

DNMT1:

DNA methyltransferases 1

RIZ1:

Retinoblastoma protein-interacting zinc-finger gene 1

ZBTB20:

Zinc finger and BTB domain containing 20

EGFR:

Epidermal growth factor receptor

CTGF:

Connective tissue growth factor

HBXIP:

Hepatitis B x-interacting protein

NUSAP1:

Nucleolar spindle-associated protein 1

Gld2:

Germ line development 2

HNF4A:

Hepatocyte nuclear factor-4a

CAT-1:

Cationic amino acid transporter 1

CCNG1:

Cyclin G1

AFP:

Alpha-fetoprotein

EZH2:

Enhancer of zeste homolog 2

CDK2:

Cyclin-dependent kinases 2

APOBEC3B:

Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B

CREB:

CAMP-responsive element-binding protein

EMT:

Epithelial–mesenchymal transition

ERα:

Estrogen receptor

APC:

Adenomatous polyposis coli

FERMT3:

Fermitin family member 3

NR1I3:

Nuclear receptor subfamily 1: group I, member 3

NRAS:

NRAS proto-oncogene

MEK:

LTBP3, latent transforming growth factor β-binding protein 3

E2F1:

E2F transcription factor 1

SMYD3:

SET and MYND domain-containing protein 3

GSK-1β:

Phosphorylated glycogen synthase kinase-3β

HDAC:

Histone deacetylase

SIRT1:

Silent information regulator-1

References

  1. Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H, et al. A global scientific strategy to cure hepatitis B. Lancet Gastroenterol Hepatol. 2019;4:545–558

    Article  PubMed  PubMed Central  Google Scholar 

  2. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(Suppl 1):4–13

    Article  CAS  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30

    Article  PubMed  Google Scholar 

  4. Kim H, Jang E, Kim SY, Choi JY, Lee NR, Kim DS, et al. Preclinical evaluation of in vitro and in vivo antiviral activities of KCT-01, a new herbal formula against hepatitis B virus. Evid Based Complement Alternat Med. 2018;2018:1073509

    Article  PubMed  PubMed Central  Google Scholar 

  5. Paik JM, Younossi Y, Henry L, Mishra A, Younossi ZM. Recent trends in the global burden of hepatitis B virus: 2007–2017. Gastroenterology. 2021;160:1845–6.e3

    Article  PubMed  Google Scholar 

  6. Stanaway JD, Flaxman AD, Naghavi M, Fitzmaurice C, Vos T, Abubakar I, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016;388:1081–1088

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sugata F, Chen HS, Kaneko S, Purcell RH, Miller RH. Analysis of the X gene promoter of woodchuck hepatitis virus. Virology. 1994;205:314–320

    Article  CAS  PubMed  Google Scholar 

  8. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol. 2004;78:12725–12734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qian Y, Wang B, Ma A, Zhang L, Xu G, Ding Q, et al. USP16 downregulation by carboxyl-terminal truncated HBx promotes the growth of hepatocellular carcinoma cells. Sci Rep. 2016;6:33039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mao X, Tey SK, Ko FCF, Kwong EML, Gao Y, Ng IO, et al. C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis. Cancer Lett. 2019;444:60–69

    Article  CAS  PubMed  Google Scholar 

  11. Motavaf M, Safari S, Saffari Jourshari M, Alavian SM. Hepatitis B virus-induced hepatocellular carcinoma: the role of the virus x protein. Acta Virol. 2013;57:389–396

    Article  CAS  PubMed  Google Scholar 

  12. Ng SA, Lee C. Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol. 2011;46:974–990

    Article  CAS  PubMed  Google Scholar 

  13. Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92

    Article  CAS  PubMed  Google Scholar 

  14. Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18:517–534

    Article  CAS  PubMed  Google Scholar 

  15. Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016;17:487–500

    Article  CAS  PubMed  Google Scholar 

  16. Sun Q, Hao Q, Prasanth KV. Nuclear long noncoding RNAs: key regulators of gene expression. Trends Genet. 2018;34:142–157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mohr AM, Mott JL. Overview of microRNA biology. Semin Liver Dis. 2015;35:3–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arechederra M, Recalde M, Gárate-Rascón M, Fernández-Barrena MG, Ávila MA, Berasain C. Epigenetic biomarkers for the diagnosis and treatment of liver disease. Cancers (Basel). 2021;13:1265

    Article  CAS  Google Scholar 

  19. Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol. 2021;27:3182–3207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Semin Immunopathol. 2020;42:173–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sivasudhan E, Blake N, Lu Z, Meng J, Rong R (2022) Hepatitis B viral protein HBx and the molecular mechanisms modulating the hallmarks of hepatocellular carcinoma: a comprehensive review. Cells 11

  22. Chong CK, Cheng CYS, Tsoi SYJ, Huang FY, Liu F, Fung J, et al. HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA. Sci Rep. 2020;10:802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA. Epigenetics in hepatocellular carcinoma development and therapy: the tip of the iceberg. JHEP Rep. 2020;2: 100167

    Article  PubMed  PubMed Central  Google Scholar 

  24. Locke WJ, Guanzon D, Ma C, Liew YJ, Duesing KR, Fung KYC, et al. DNA methylation cancer biomarkers: translation to the clinic. Front Genet. 2019;10:1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wijetunga NA, Pascual M, Tozour J, Delahaye F, Alani M, Adeyeye M, et al. A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets. Oncogene. 2017;36:2030–2044

    Article  CAS  PubMed  Google Scholar 

  26. Kuramoto J, Arai E, Tian Y, Funahashi N, Hiramoto M, Nammo T, et al. Genome-wide DNA methylation analysis during non-alcoholic steatohepatitis-related multistage hepatocarcinogenesis: comparison with hepatitis virus-related carcinogenesis. Carcinogenesis. 2017;38:261–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fu X, Song X, Li Y, Tan D, Liu G. Hepatitis B virus X protein upregulates DNA methyltransferase 3A/3B and enhances SOCS-1CpG island methylation. Mol Med Rep. 2016;13:301–308

    Article  CAS  PubMed  Google Scholar 

  28. Zhao Z, Hu Y, Shen X, Lao Y, Zhang L, Qiu X, et al. HBx represses RIZ1 expression by DNA methyltransferase 1 involvement in decreased miR-152 in hepatocellular carcinoma. Oncol Rep. 2017;37:2811–2818

    Article  CAS  PubMed  Google Scholar 

  29. Park IY, Sohn BH, Yu E, Suh DJ, Chung YH, Lee JH, et al. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007;132:1476–1494

    Article  CAS  PubMed  Google Scholar 

  30. Choi JH, Jeong H, Jang KL. Hepatitis B virus X protein suppresses all-trans retinoic acid-induced apoptosis in human hepatocytes by repressing p14 expression via DNA methylation. J Gen Virol. 2017;98:2786–2798

    Article  CAS  PubMed  Google Scholar 

  31. Xie Q, Chen L, Shan X, Shan X, Tang J, Zhou F, et al. Epigenetic silencing of SFRP1 and SFRP5 by hepatitis B virus X protein enhances hepatoma cell tumorigenicity through Wnt signaling pathway. Int J Cancer. 2014;135:635–646

    Article  CAS  PubMed  Google Scholar 

  32. Yan Y, Huang P, Mao K, He C, Xu Q, Zhang M, et al. Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression. Oncogene. 2021;40:28–45

    Article  CAS  PubMed  Google Scholar 

  33. Vivekanandan P, Daniel HD, Kannangai R, Martinez-Murillo F, Torbenson M. Hepatitis B virus replication induces methylation of both host and viral DNA. J Virol. 2010;84:4321–4329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu X, Xu Q, Chen W, Cao H, Zheng R, Li G. Hepatitis B virus DNA-induced carcinogenesis of human normal liver cells by virtue of nonmethylated CpG DNA. Oncol Rep. 2009;21:941–947

    CAS  PubMed  Google Scholar 

  35. Koumbi L, Karayiannis P. The epigenetic control of hepatitis B virus modulates the outcome of infection. Front Microbiol. 2015;6:1491

    PubMed  Google Scholar 

  36. Shamay M, Krithivas A, Zhang J, Hayward SD. Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi’s sarcoma-associated herpesvirus LANA. Proc Natl Acad Sci USA. 2006;103:14554–14559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S, et al. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res. 2009;69:2766–2774

    Article  CAS  PubMed  Google Scholar 

  38. Zhu YZ, Zhu R, Shi LG, Mao Y, Zheng GJ, Chen Q, et al. Hepatitis B virus X protein promotes hypermethylation of p16(INK4A) promoter through upregulation of DNA methyltransferases in hepatocarcinogenesis. Exp Mol Pathol. 2010;89:268–275

    Article  CAS  PubMed  Google Scholar 

  39. Jung JK, Park SH, Jang KL. 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;91:493–500

    Article  CAS  PubMed  Google Scholar 

  40. Park SH, Jung JK, Lim JS, Tiwari I, Jang KL. Hepatitis B virus X protein overcomes all-trans retinoic acid-induced cellular senescence by downregulating levels of p16 and p21 via DNA methylation. J Gen Virol. 2011;92:1309–1317

    Article  CAS  PubMed  Google Scholar 

  41. Arzumanyan A, Friedman T, Kotei E, Ng IO, Lian Z, Feitelson MA. Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene. 2012;31:563–572

    Article  CAS  PubMed  Google Scholar 

  42. Song G, Zhu X, Xuan Z, Zhao L, Dong H, Chen J, et al. Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma. Theranostics. 2021;11:2318–2333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pogribny IP, Rusyn I. Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. Cancer Lett. 2014;342:223–230

    Article  CAS  PubMed  Google Scholar 

  44. Markouli M, Strepkos D, Basdra EK, Papavassiliou AG, Piperi C. Prominent role of histone modifications in the regulation of tumor metastasis. Int J Mol Sci. 2021;22:2278

    Article  CAS  Google Scholar 

  45. Rajan PK, Udoh UA, Sanabria JD, Banerjee M, Smith G, Schade MS, et al. The role of histone acetylation-/methylation-mediated apoptotic gene regulation in hepatocellular carcinoma. Int J Mol Sci. 2020;21:8894

    Article  CAS  PubMed Central  Google Scholar 

  46. Zhang Y, Sun Z, Jia J, Du T, Zhang N, Tang Y, et al. Overview of histone modification. Adv Exp Med Biol. 2021;1283:1–16

    Article  CAS  PubMed  Google Scholar 

  47. Neganova ME, Klochkov SG, Aleksandrova YR, Aliev G. Histone modifications in epigenetic regulation of cancer: perspectives and achieved progress. Semin Cancer Biol. 2020. https://doi.org/10.1016/j.semcancer.2020.07.015

    Article  PubMed  Google Scholar 

  48. Gao W, Jia Z, Tian Y, Yang P, Sun H, Wang C, et al. HBx protein contributes to liver carcinogenesis by H3K4me3 modification through stabilizing WD repeat domain 5 protein. Hepatology. 2020;71:1678–1695

    Article  CAS  PubMed  Google Scholar 

  49. Hamamoto H, Maemura K, Matsuo K, Taniguchi K, Tanaka Y, Futaki S, et al. Delta-like 3 is silenced by HBx via histone acetylation in HBV-associated HCCs. Sci Rep. 2018;8:4842

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Mizuno Y, Maemura K, Tanaka Y, Hirata A, Futaki S, Hamamoto H, et al. Expression of delta-like 3 is downregulated by aberrant DNA methylation and histone modification in hepatocellular carcinoma. Oncol Rep. 2018;39:2209–2216

    CAS  PubMed  Google Scholar 

  51. Takeuchi Y, Tsuge M, Tsushima K, Suehiro Y, Fujino H, Ono A, et al. Signal activation of hepatitis B Virus-related hepatocarcinogenesis by up-regulation of SUV39h1. J Infect Dis. 2020;222:2061–2070

    Article  CAS  PubMed  Google Scholar 

  52. Wang DY, Zou LP, Liu XJ, Zhu HG, Zhu R. Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Exp Mol Pathol. 2015;99:399–408

    Article  CAS  PubMed  Google Scholar 

  53. Ye Y, Yang J, Hu Q, Mao J, Yang Q, Chen H, et al. SIP1 serves a role in HBx-induced liver cancer growth and metastasis. Int J Oncol. 2019;55:1019–1032

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Han TS, Hur K, Cho HS, Ban HS. Epigenetic associations between lncRNA/circRNA and miRNA in hepatocellular carcinoma. Cancers (Basel). 2020;12:2622

    Article  CAS  Google Scholar 

  55. Ghafouri-Fard S, Honarmand Tamizkar K, Hussen BM, Taheri M. MicroRNA signature in liver cancer. Pathol Res Pract. 2021;219: 153369

    Article  CAS  PubMed  Google Scholar 

  56. Jun L, Yang G, Zhisu L. The utility of serum exosomal microRNAs in hepatocellular carcinoma. Biomed Pharmacother. 2019;111:1221–1227

    Article  PubMed  CAS  Google Scholar 

  57. Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8:45–56

    Article  PubMed  PubMed Central  Google Scholar 

  58. Silva Rodrigues DV, Silva Monteiro VV, Navegantes-Lima KC, de Brito Oliveira AL, de França Gaspar SL, Gonçalves Quadros LB, et al. MicroRNAs in cell cycle progression and proliferation: molecular mechanisms and pathways. Non-Coding RNA Investig. 2018;2:28

    Article  Google Scholar 

  59. Zhang QY, Men CJ, Ding XW. Upregulation of microRNA-140-3p inhibits epithelial-mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma through inactivation of the MAPK signaling pathway by targeting GRN. J Cell Biochem. 2019;120:14885–14898

    Article  CAS  PubMed  Google Scholar 

  60. Wang J, Chu Y, Xu M, Zhang X, Zhou Y, Xu M. miR-21 promotes cell migration and invasion of hepatocellular carcinoma by targeting KLF5. Oncol Lett. 2019;17:2221–2227

    CAS  PubMed  Google Scholar 

  61. Tait Wojno ED, Hunter CA, Stumhofer JS. The Immunobiology of the interleukin-12 family: room for discovery. Immunity. 2019;50:851–870

    Article  CAS  PubMed  Google Scholar 

  62. Yin D, Wang Y, Sai W, Zhang L, Miao Y, Cao L, et al. HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12. Oncol Rep. 2016;36:2305–2312

    Article  CAS  PubMed  Google Scholar 

  63. Hou Z, Quan J. Hepatitis B virus X protein increases microRNA-21 expression and accelerates the development of hepatoma via the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B signaling pathway. Mol Med Rep. 2017;15:3285–3291

    Article  CAS  PubMed  Google Scholar 

  64. Ochi M, Otsuka M, Maruyama R, Koike K. HBx increases EGFR expression by inhibiting miR129-5p function. Biochem Biophys Res Commun. 2020;529:198–203

    Article  CAS  PubMed  Google Scholar 

  65. Tian Y, Xiao X, Gong X, Peng F, Xu Y, Jiang Y, et al. HBx promotes cell proliferation by disturbing the cross-talk between miR-181a and PTEN. Sci Rep. 2017;7:40089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lin X, Zuo S, Luo R, Li Y, Yu G, Zou Y, et al. HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma. Theranostics. 2019;9:7583–7598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dong KS, Chen Y, Yang G, Liao ZB, Zhang HW, Liang HF, et al. TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p. Oncogene. 2020;39:1807–1820

    Article  CAS  PubMed  Google Scholar 

  68. Zhou SJ, Deng YL, Liang HF, Jaoude JC, Liu FY. Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and Notch signaling in hepatocellular carcinoma. Cell Death Differ. 2017;24:1577–1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang Y, Luo M, Zhang K, Zhang J, Gao T, Connell DO, et al. Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma. Nat Commun. 2020;11:433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Huang G, Xiang Z, Wu H, He Q, Dou R, Lin Z, et al. The lncRNA BDNF-AS/WDR5/FBXW7 axis mediates ferroptosis in gastric cancer peritoneal metastasis by regulating VDAC3 ubiquitination. Int J Biol Sci. 2022;18:1415–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhang Q, Song G, Yao L, Liu Y, Liu M, Li S, et al. miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3. J Exp Clin Cancer Res. 2018;37:14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kong XX, Lv YR, Shao LP, Nong XY, Zhang GL, Zhang Y, et al. HBx-induced MiR-1269b in NF-κB dependent manner upregulates cell division cycle 40 homolog (CDC40) to promote proliferation and migration in hepatoma cells. J Transl Med. 2016;14:189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Chen WS, Liu LC, Yen CJ, Chen YJ, Chen JY, Ho CY, et al. Nuclear IKKα mediates microRNA-7/-103/107/21 inductions to downregulate maspin expression in response to HBx overexpression. Oncotarget. 2016;7:56309–56323

    Article  PubMed  PubMed Central  Google Scholar 

  74. Yip WK, Cheng AS, Zhu R, Lung RW, Tsang DP, Lau SS, et al. Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in hepatocellular carcinoma development. PLoS ONE. 2011;6: e22888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu FY, Zhou SJ, Deng YL, Zhang ZY, Zhang EL, Wu ZB, et al. MiR-216b is involved in pathogenesis and progression of hepatocellular carcinoma through HBx-miR-216b-IGF2BP2 signaling pathway. Cell Death Dis. 2015;6: e1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gao Y, Gu J, Wang Y, Fu D, Zhang W, Zheng G, et al. Hepatitis B virus X protein boosts hepatocellular carcinoma progression by downregulating microRNA-137. Pathol Res Pract. 2020;216: 152981

    Article  CAS  PubMed  Google Scholar 

  77. Shi T, Hua Q, Ma Z, Lv Q. Downregulation of miR-200a-3p induced by hepatitis B Virus X (HBx) Protein promotes cell proliferation and invasion in HBV-infection-associated hepatocarcinoma. Pathol Res Pract. 2017;213:1464–1469

    Article  CAS  PubMed  Google Scholar 

  78. Liu X, Zhang Y, Wang P, Wang H, Su H, Zhou X, et al. HBX protein-induced downregulation of microRNA-18a is responsible for upregulation of connective tissue growth factor in HBV infection-associated hepatocarcinoma. Med Sci Monit. 2016;22:2492–2500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang C, Liu P, Zhang C. Hepatitis B virus X protein upregulates alpha-fetoprotein to promote hepatocellular carcinoma by targeting miR-1236 and miR-329. J Cell Biochem. 2020;121:2489–2499

    Article  CAS  PubMed  Google Scholar 

  80. Yang Z, Li J, Feng G, Wang Y, Yang G, Liu Y, et al. Hepatitis B virus X protein enhances hepatocarcinogenesis by depressing the targeting of NUSAP1 mRNA by miR-18b. Cancer Biol Med. 2019;16:276–287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Zhang Y, Ren H, Li J, Xue R, Liu H, Zhu Z, et al. Elevated HMGB1 expression induced by hepatitis B virus X protein promotes epithelial-mesenchymal transition and angiogenesis through STAT3/miR-34a/NF-κB in primary liver cancer. Am J Cancer Res. 2021;11:479–494

    PubMed  PubMed Central  Google Scholar 

  82. Dai R, Peng F, Xiao X, Gong X, Jiang Y, Zhang M, et al. Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells. Oncotarget. 2017;8:60962–60974

    Article  PubMed  PubMed Central  Google Scholar 

  83. Bandopadhyay M, Sarkar N, Datta S, Das D, Pal A, Panigrahi R, et al. Hepatitis B virus X protein mediated suppression of miRNA-122 expression enhances hepatoblastoma cell proliferation through cyclin G1–p53 axis. Infect Agent Cancer. 2016;11:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Hu XM, Yan XH, Hu YW, Huang JL, Cao SW, Ren TY, et al. miRNA-548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x-interacting protein. Hepatol Res. 2016;46:804–815

    Article  CAS  PubMed  Google Scholar 

  85. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wu Y, Zhang Y, Qin X, Geng H, Zuo D, Zhao Q. PI3K/AKT/mTOR pathway-related long non-coding RNAs: roles and mechanisms in hepatocellular carcinoma. Pharmacol Res. 2020;160: 105195

    Article  CAS  PubMed  Google Scholar 

  87. Mattick JS, Rinn JL. Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol. 2015;22:5–7

    Article  CAS  PubMed  Google Scholar 

  88. Xu WH, Zhang JB, Dang Z, Li X, Zhou T, Liu J, et al. Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma. Int J Biol Sci. 2014;10:664–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cao C, Sun J, Zhang D, Guo X, Xie L, Li X, et al. The long intergenic noncoding RNA UFC1, a target of MicroRNA 34a, interacts with the mRNA stabilizing protein HuR to increase levels of β-catenin in HCC cells. Gastroenterology. 2015;148:415–26.e18

    Article  CAS  PubMed  Google Scholar 

  90. Yuan D, Chen Y, Li X, Li J, Zhao Y, Shen J, et al. Long Non-coding RNAs: potential biomarkers and targets for hepatocellular carcinoma therapy and diagnosis. Int J Biol Sci. 2021;17:220–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang H, Chen X, Zhang J, Wang X, Chen H, Liu L, et al. Long non-coding RNAs in HBV-related hepatocellular carcinoma (review). Int J Oncol. 2020;56:18–32

    PubMed  Google Scholar 

  92. Zhang B, Han S, Feng B, Chu X, Chen L, Wang R. Hepatitis B virus X protein-mediated non-coding RNA aberrations in the development of human hepatocellular carcinoma. Exp Mol Med. 2017;49: e293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jin Y, Wu D, Yang W, Weng M, Li Y, Wang X, et al. Hepatitis B virus x protein induces epithelial-mesenchymal transition of hepatocellular carcinoma cells by regulating long non-coding RNA. Virol J. 2017;14:238

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Hu JJ, Song W, Zhang SD, Shen XH, Qiu XM, Wu HZ, et al. HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling. Sci Rep. 2016;6:23521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, et al. Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem. 2012;287:26302–26311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343:1221–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liu Y, Feng J, Sun M, Yang G, Yuan H, Wang Y, et al. Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma. Cancer Lett. 2019;454:158–170

    Article  CAS  PubMed  Google Scholar 

  98. Zhang Y, Li J, Wang S, Yang F, Zhou Y, Liu Y, et al. HBx-associated long non-coding RNA activated by TGF-β promotes cell invasion and migration by inducing autophagy in primary liver cancer. Int J Oncol. 2020;56:337–347

    CAS  PubMed  Google Scholar 

  99. Hu Z, Huang P, Yan Y, Zhou Z, Wang J, Wu G. Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion. Biochem Biophys Res Commun. 2019;508:79–86

    Article  CAS  PubMed  Google Scholar 

  100. Zhang F, Li Y, Gan L, Tong X, Qi D, Wang Q, et al. HBx-upregulated MAFG-AS1 promotes cell proliferation and migration of hepatoma cells by enhancing MAFG expression and stabilizing nonmuscle myosin IIA. FASEB J. 2021;35: e21529

    CAS  PubMed  Google Scholar 

  101. Chen T, Pei J, Wang J, Luo R, Liu L, Wang L, et al. HBx-related long non-coding RNA 01152 promotes cell proliferation and survival by IL-23 in hepatocellular carcinoma. Biomed Pharmacother. 2019;115: 108877

    Article  CAS  PubMed  Google Scholar 

  102. Tu W, Yang Y, Song Y, Zhu W. Hepatitis B virus x protein accelerated the proliferation of hepatocellular carcinoma cell through lncRNA SNHG20/PTEN pathway. J Biochem. 2019;165:423–431

    Article  CAS  PubMed  Google Scholar 

  103. Huang JL, Ren TY, Cao SW, Zheng SH, Hu XM, Hu YW, et al. HBx-related long non-coding RNA DBH-AS1 promotes cell proliferation and survival by activating MAPK signaling in hepatocellular carcinoma. Oncotarget. 2015;6:33791–33804

    Article  PubMed  PubMed Central  Google Scholar 

  104. Song W, Zheng C, Liu M, Xu Y, Qian Y, Zhang Z, et al. TRERNA1 upregulation mediated by HBx promotes sorafenib resistance and cell proliferation in HCC via targeting NRAS by sponging miR-22-3p. Mol Ther. 2021;29:2601–2616

    Article  CAS  PubMed  Google Scholar 

  105. He B, Peng F, Li W, Jiang Y. Interaction of lncRNA-MALAT1 and miR-124 regulates HBx-induced cancer stem cell properties in HepG2 through PI3K/Akt signaling. J Cell Biochem. 2019;120:2908–2918

    Article  CAS  PubMed  Google Scholar 

  106. Hou Z, Xu X, Fu X, Tao S, Zhou J, Liu S, et al. HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma. Am J Cancer Res. 2017;7:845–856

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen Z, Yu W, Zhou Q, Zhang J, Jiang H, Hao D, et al. A novel lncRNA IHS promotes tumor proliferation and metastasis in HCC by regulating the ERK- and AKT/GSK-3β-signaling pathways. Mol Ther Nucleic Acids. 2019;16:707–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Deng Y, Wei Z, Huang M, Xu G, Wei W, Peng B, et al. Long non-coding RNA F11-AS1 inhibits HBV-related hepatocellular carcinoma progression by regulating NR1I3 via binding to microRNA-211-5p. J Cell Mol Med. 2020;24:1848–1865

    Article  CAS  PubMed  Google Scholar 

  109. Huang P, Xu Q, Yan Y, Lu Y, Hu Z, Ou B, et al. HBx/ERα complex-mediated LINC01352 downregulation promotes HBV-related hepatocellular carcinoma via the miR-135b-APC axis. Oncogene. 2020;39:3774–3789

    Article  CAS  PubMed  Google Scholar 

  110. 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

    Article  PubMed  CAS  Google Scholar 

  111. Tsuge M, Hiraga N, Akiyama R, Tanaka S, Matsushita M, Mitsui F, et al. HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice. J Gen Virol. 2010;91:1854–1864

    Article  CAS  PubMed  Google Scholar 

  112. Belloni L, Pollicino T, De Nicola F, Guerrieri F, Raffa G, Fanciulli M, et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci USA. 2009;106:19975–19979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Salerno D, Chiodo L, Alfano V, Floriot O, Cottone G, Paturel A, et al. Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription. Gut. 2020;69:2016–2024

    Article  CAS  PubMed  Google Scholar 

  114. Lee H, Jeong H, Lee SY, Kim SS, Jang KL. Hepatitis B virus X protein stimulates virus replication Via DNA methylation of the C-1619 in covalently closed circular DNA. Mol Cells. 2019;42:67–78

    CAS  PubMed  Google Scholar 

  115. Cheng ST, Hu JL, Ren JH, Yu HB, Zhong S, Wai Wong VK, et al. Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx. J Hepatol. 2021;74:522–534

    Article  CAS  PubMed  Google Scholar 

  116. Andrisani O (2021) Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma. Hepatoma Res 7

  117. Cossío FP, Esteller M, Berdasco M. Towards a more precise therapy in cancer: exploring epigenetic complexity. Curr Opin Chem Biol. 2020;57:41–49

    Article  PubMed  CAS  Google Scholar 

  118. Nervi C, De Marinis E, Codacci-Pisanelli G. Epigenetic treatment of solid tumours: a review of clinical trials. Clin Epigenet. 2015;7:127

    Article  CAS  Google Scholar 

  119. Srisuttee R, Koh SS, Kim SJ, Malilas W, Boonying W, Cho IR, et al. Hepatitis B virus X (HBX) protein upregulates β-catenin in a human hepatic cell line by sequestering SIRT1 deacetylase. Oncol Rep. 2012;28:276–282

    CAS  PubMed  Google Scholar 

  120. Srisuttee R, Koh SS, Malilas W, Moon J, Cho IR, Jhun BH, et al. SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis. Biochem Biophys Res Commun. 2012;429:45–50

    Article  CAS  PubMed  Google Scholar 

  121. Lin HC, Chen YF, Hsu WH, Yang CW, Kao CH, Tsai TF. Resveratrol helps recovery from fatty liver and protects against hepatocellular carcinoma induced by hepatitis B virus X protein in a mouse model. Cancer Prev Res (Phila). 2012;5:952–962

    Article  CAS  Google Scholar 

  122. Park S, Lim J, Kim JR, Cho S. Inhibitory effects of resveratrol on hepatitis B virus X protein-induced hepatocellular carcinoma. J Vet Sci. 2017;18:419–429

    Article  PubMed  PubMed Central  Google Scholar 

  123. Jiang Z, Liu H. Metformin inhibits tumorigenesis in HBV-induced hepatocellular carcinoma by suppressing HULC overexpression caused by HBX. J Cell Biochem. 2018;119:4482–4495

    Article  CAS  PubMed  Google Scholar 

  124. Lee H, Sohn JB, Kim SS, Jang KL. DNA methyltransferase inhibitor assay system based on the HBx-induced DNA methylation of E-cadherin. Biochem Biophys Res Commun. 2013;438:540–545

    Article  CAS  PubMed  Google Scholar 

  125. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours—past lessons and future promise. Nat Rev Clin Oncol. 2020;17:91–107

    Article  CAS  PubMed  Google Scholar 

  126. Araki K, Miyazaki J, Tsurimoto T, Inomoto T, Iwanaga T, Matsubara K, et al. Demethylation by 5-azacytidine results in the expression of hepatitis B virus surface antigen in transgenic mice. Jpn J Cancer Res. 1989;80:295–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Miyoshi E, Fujii J, Hayashi N, Ueda K, Towata T, Fusamoto H, et al. Enhancement of hepatitis-B surface-antigen expression by 5-azacytidine in a hepatitis-B-virus-transfected cell line. Int J Cancer. 1992;52:137–140

    Article  CAS  PubMed  Google Scholar 

  128. Hong X, Kim ES, Guo H. Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B. Hepatology. 2017;66:2066–2077

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by National Natural Science Foundation of China (No. 81972643), Sichuan Science and Technology Project (2021YJ0201) and Luxian People's Government and Southwest Medical University Scientific and Technological Achievements Transfer and Transformation Strategic Cooperation Project (2019LXXNYKD-07).

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China

    Liqiong Yang, Tao Zou, Yao Chen, Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Zhangang Xiao & Jing Shen

  2. Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China

    Liqiong Yang, Tao Zou, Yao Chen, Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Zhangang Xiao & Jing Shen

  3. South Sichuan Institute of Translational Medicine, Luzhou, 646000, China

    Liqiong Yang, Tao Zou, Yao Chen, Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Zhangang Xiao & Jing Shen

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  1. Liqiong Yang
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  2. Tao Zou
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Contributions

L-QY drafted the manuscript. TZ, YC, Y-SZ and XW collected literatures and draw figure. M-XL, F-KD, YuC edited manuscript and provided valuable suggestions. Z-GX and JS conceived the idea, edited manuscript for important intellectual content.

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Correspondence to Zhangang Xiao or Jing Shen.

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The authors Liqiong Yang, Tao Zou, Yao Chen, Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Zhangang Xiao and Jing Shen declare that they have no conflict of interest.

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Yang, L., Zou, T., Chen, Y. et al. Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol Int 16, 741–754 (2022). https://doi.org/10.1007/s12072-022-10351-6

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