Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis

World Journal of Gastroenterology

Volumn 20, Issue 33, 2014, Pages 11630-11640

  Tarocchi, Mirko ^a   Polvani, Simone ^a   Marroncini, Giada ^a,b   Galli, Andrea ^a,b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b FiorGen Foundation   (Italy)

Author keywords

Cell biology; Chronic hepatitis B infection; Hepatitis B virus; Hepatocarcinogenesis; Hepatocellular carcinoma

Indexed keywords

CIRCULAR DNA; HEPATITIS B VIRUS X PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MICRORNA; MICRORNA 143; MICRORNA 19; MICRORNA 34; STAT3 PROTEIN; UNCLASSIFIED DRUG; VIRUS DNA; VOLTAGE DEPENDENT ANION CHANNEL 3; ANTIVIRUS AGENT;

CANCER INHIBITION; CANCER RISK; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHROMOSOMAL INSTABILITY; CHRONIC INFLAMMATION; DISEASE ASSOCIATION; DNA METHYLATION; DNA STRAND; GENETIC POLYMORPHISM; HEPATITIS B; HEPATITIS B VIRUS GENOTYPE B; HEPATITIS B VIRUS GENOTYPE C; HEPATITIS B VIRUS GENOTYPE D; HUMAN; LIVER CANCER; LIVER CARCINOGENESIS; LIVER CELL; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER MITOCHONDRION; MALIGNANT TRANSFORMATION; META ANALYSIS (TOPIC); MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; NONHUMAN; OXIDATIVE STRESS; REVIEW; TUMOR IMMUNITY; VIRUS CARCINOGENESIS; VIRUS GENOME; VIRUS INHIBITION; VIRUS LOAD; VIRUS NUCLEOCAPSID; VIRUS REPLICATION; ANIMAL; CARCINOMA, HEPATOCELLULAR; DRUG EFFECTS; HEPATITIS B VIRUS; IMMUNOLOGY; LIVER NEOPLASMS; PATHOGENICITY; PATHOLOGY; VIROLOGY; VIRUS CELL TRANSFORMATION;

ANIMALS; ANTIVIRAL AGENTS; CARCINOMA, HEPATOCELLULAR; CELL TRANSFORMATION, VIRAL; HEPATITIS B; HEPATITIS B VIRUS; HUMANS; LIVER NEOPLASMS;

EID: 84908253441     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v20.i33.11630     Document Type: Review

References (120)

1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Accessed on 27/02/2014. 2013. Available from: URL: http://globocan.iarc.fr
2. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013; 47 Suppl: S2-S6 [PMID: 23632345 DOI: 10.1097/MCG.0b013e3182872f29]
3. Fares N, Péron JM. [Epidemiology, natural history, and risk factors of hepatocellular carcinoma]. Rev Prat 2013; 63: 216-217, 220-222 [PMID: 23513788]
4. Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, Boney A, Sullivan J, Frush DP, Chen YT, Kishnani PS. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis 2005; 28: 153-162 [PMID: 15877204 DOI: 10.1007/s10545-005-7500-2]
5. Dorfman JD, Schulick R, Choti MA, Geschwind JF, Kamel I, Torbenson M, Thuluvath PJ. Differences in characteristics of patients with and without known risk factors for hepatocellular carcinoma in the United States. World J Gastroenterol 2007; 13: 781-784 [PMID: 17278203]
6. Montalto G, Cervello M, Giannitrapani L, Dantona F, Terranova A, Castagnetta LA. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci 2002; 963: 13-20 [PMID: 12095924]
7. Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med 2004; 350: 1118-1129 [PMID: 15014185 DOI: 10.1056/NEJMra031087]
8. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48: 335-352 [PMID: 18096267]
9. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006; 118: 3030-3044 [PMID: 16404738 DOI: 10.1002/ijc.21731]
10. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65-73 [PMID: 16391218]
11. Kao JH, Chen PJ, Chen DS. Recent advances in the research of hepatitis B virus-related hepatocellular carcinoma: epidemiologic and molecular biological aspects. Adv Cancer Res 2010; 108: 21-72 [PMID: 21034965]
12. Yang JD, Roberts LR. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol Hepatol 2010; 7: 448-458 [PMID: 20628345]
13. Sherman M, Bruix J, Porayko M, Tran T. Screening for hepatocellular carcinoma: the rationale for the American Association for the Study of Liver Diseases recommendations. Hepatology 2012; 56: 793-796 [PMID: 22689409 DOI: 10.1002/hep.25869]
14. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-1956 [PMID: 2834034]
15. Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ, Chen PJ, Hsiao TJ, Lee PH, Chen CJ. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 2000; 92: 1159-1164 [PMID: 10904089]
16. Kew MC, Macerollo P. Effect of age on the etiologic role of the hepatitis B virus in hepatocellular carcinoma in blacks. Gastroenterology 1988; 94: 439-442 [PMID: 2446950]
17. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142: 1264-1273.e1 [PMID: 22537432]
18. Roman S, Panduro A. HBV endemicity in Mexico is associated with HBV genotypes H and G. World J Gastroenterol 2013; 19: 5446-5453 [PMID: 24023487 DOI: 10.3748/wjg.v19.i33.5446]
19. Tan YJ. Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol 2011; 17: 4853-4857 [PMID: 22171125 DOI: 10.3748/wjg.v17.i44.4853]
20. Yeung P, Wong DK, Lai CL, Fung J, Seto WK, Yuen MF. Association of hepatitis B virus pre-S deletions with the development of hepatocellular carcinoma in chronic hepatitis B. J Infect Dis 2011; 203: 646-654 [PMID: 21227916]
21. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, Yuen JC, Mizokami M, Lai CL. Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut 2008; 57: 98-102 [PMID: 17483190]
22. Arciello M, Gori M, Maggio R, Barbaro B, Tarocchi M, Galli A, Balsano C. Environmental pollution: a tangible risk for NAFLD pathogenesis. Int J Mol Sci 2013; 14: 22052-22066 [PMID: 24213605]
23. Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol 2008; 14: 4300-4308 [PMID: 18666317]
24. Zanetti AR, Van Damme P, Shouval D. The global impact of vaccination against hepatitis B: a historical overview. Vaccine 2008; 26: 6266-6273 [PMID: 18848855]
25. Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene 2006; 25: 3866-3884 [PMID: 16799628]
26. Summers J, Mason WS. Replication of the genome of a hepatitis B - like virus by reverse transcription of an RNA intermediate. Cell 1982; 29: 403-415 [PMID: 6180831]
27. Chen JY, Chen WN, Liu LL, Lin WS, Jiao BY, Wu YL, Lin JY, Lin X. Hepatitis B spliced protein (HBSP) generated by a spliced hepatitis B virus RNA participates in abnormality of fibrin formation and functions by binding to fibrinogen γ chain. J Med Virol 2010; 82: 2019-2026 [PMID: 20981788 DOI: 10.1002/jmv.21918]
28. Abu-Amara M, Feld JJ. Does antiviral therapy for chronic hepatitis B reduce the risk of hepatocellular carcinoma? Semin Liver Dis 2013; 33: 157-166 [PMID: 23749672 DOI: 10.1055/s-0033-1345719]
29. Beck J, Nassal M. Hepatitis B virus replication. World J Gastroenterol 2007; 13: 48-64 [PMID: 17206754]
30. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009; 51: 581-592 [PMID: 19616338]
31. Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013; 4: 176-185 [PMID: 23483479 DOI: 10.1007/s13238-013-2084-3]
32. He G, Karin M. NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res 2011; 21: 159-168 [PMID: 21187858]
33. Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 2011; 7: 651-658 [PMID: 21647333]
34. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22: 291-303 [PMID: 22975373]
35. Zhang HH, Mei MH, Fei R, Liu F, Wang JH, Liao WJ, Qin LL, Wei L, Chen HS. Regulatory T cells in chronic hepatitis B patients affect the immunopathogenesis of hepatocellular carcinoma by suppressing the anti-tumour immune responses. J Viral Hepat 2010; 17 Suppl 1: 34-43 [PMID: 20586932]
36. Li SP, Peng QQ, Ding T, Xu J, Zhang CQ, Feng KT, Li JQ. [Clinical significance of regulatory T cells proportion in the peripheral blood and tumor tissue in primary hepatocellular carcinoma]. Zhonghua Zhongliu Zazhi 2008; 30: 523-527 [PMID: 19062720]
37. Duygu F, Karsen H, Aksoy N, Taskin A. Relationship of oxidative stress in hepatitis B infection activity with HBV DNA and fibrosis. Ann Lab Med 2012; 32: 113-118 [PMID: 22389877 DOI: 10.3343/alm.2012.32.2.113]
38. Fujita N, Sugimoto R, Ma N, Tanaka H, Iwasa M, Kobayashi Y, Kawanishi S, Watanabe S, Kaito M, Takei Y. Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C. J Viral Hepat 2008; 15: 498-507 [PMID: 18331251]
39. Choi J, Ou JH. Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. Am J Physiol Gastrointest Liver Physiol 2006; 290: G847-G851 [PMID: 16603728]
40. Tien Kuo M, Savaraj N. Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers. Mol Carcinog 2006; 45: 701-709 [PMID: 16652372 DOI: 10.1002/mc.20240]
41. Czaja MJ. Cell signaling in oxidative stress-induced liver injury. Semin Liver Dis 2007; 27: 378-389 [PMID: 17979074 DOI: 10.1055/s-2007-991514]
42. Polvani S, Tarocchi M, Galli A. PPARγ and Oxidative Stress: Con(β) Catenating NRF2 and FOXO. PPAR Res 2012; 2012: 641087 [PMID: 22481913 DOI: 10.1155/2012/641087]
43. Dröge W. Oxidative stress and aging. Adv Exp Med Biol 2003; 543: 191-200 [PMID: 14713123]
44. Ha HL, Shin HJ, Feitelson MA, Yu DY. Oxidative stress and antioxidants in hepatic pathogenesis. World J Gastroenterol 2010; 16: 6035-6043 [PMID: 21182217]
45. Dunsford HA, Sell S, Chisari FV. Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res 1990; 50: 3400-3407 [PMID: 1692259]
46. Galli A, Ceni E, Mello T, Polvani S, Tarocchi M, Buccoliero F, Lisi F, Cioni L, Ottanelli B, Foresta V, Mastrobuoni G, Moneti G, Pieraccini G, Surrenti C, Milani S. Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin. Hepatology 2010; 52: 493-505 [PMID: 20683949 DOI: 10.1002/hep.23669]
47. Ha HL, Yu DY. HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway. World J Gastroenterol 2010; 16: 4932-4937 [PMID: 20954279]
48. Adam-Vizi V, Chinopoulos C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci 2006; 27: 639-645 [PMID: 17056127]
49. Lee YI, Hwang JM, Im JH, Lee YI, Kim NS, Kim DG, Yu DY, Moon HB, Park SK. Human hepatitis B virus-X protein alters mitochondrial function and physiology in human liver cells. J Biol Chem 2004; 279: 15460-15471 [PMID: 14724286 DOI: 10.1074/jbc.M309280200]
50. Rahmani Z, Huh KW, Lasher R, Siddiqui A. Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J Virol 2000; 74: 2840-2846 [PMID: 10684300]
51. Clippinger AJ, Bouchard MJ. Hepatitis B virus HBx protein localizes to mitochondria in primary rat hepatocytes and modulates mitochondrial membrane potential. J Virol 2008; 82: 6798-6811 [PMID: 18448529]
52. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett 2011; 305: 123-143 [PMID: 21168955]
53. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004; 78: 12725-12734 [PMID: 15542625]
54. Waris G, Huh KW, Siddiqui A. Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress. Mol Cell Biol 2001; 21: 7721-7730 [PMID: 11604508 DOI: 10.1128/MCB.21.22.7721-7730.2001]
55. Li J, Liu Y, Wang Z, Liu K, Wang Y, Liu J, Ding H, Yuan Z. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol 2011; 85: 6319-6333 [PMID: 21507968]
56. Chen J, Siddiqui A. Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress. J Virol 2007; 81: 6757-6760 [PMID: 17428866]
57. Yi YS, Park SG, Byeon SM, Kwon YG, Jung G. Hepatitis B virus X protein induces TNF-alpha expression via downregulation of selenoprotein P in human hepatoma cell line, HepG2. Biochim Biophys Acta 2003; 1638: 249-256 [PMID: 12878326]
58. Hsieh YH, Su IJ, Wang HC, Chang WW, Lei HY, Lai MD, Chang WT, Huang W. Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 2004; 25: 2023-2032 [PMID: 15180947 DOI: 10.1093/carcin/bgh207]
59. Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, Lee NP, Lee WH, Ariyaratne PN, Tennakoon C, Mulawadi FH, Wong KF, Liu AM, Poon RT, Fan ST, Chan KL, Gong Z, Hu Y, Lin Z, Wang G, Zhang Q, Barber TD, Chou WC, Aggarwal A, Hao K, Zhou W, Zhang C, Hardwick J, Buser C, Xu J, Kan Z, Dai H, Mao M, Reinhard C, Wang J, Luk JM. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 2012; 44: 765-769 [PMID: 22634754]
60. Feitelson MA, Lee J. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett 2007; 252: 157-170 [PMID: 17188425]
61. Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol 2005; 42: 760-777 [PMID: 15826727]
62. Li W, Zeng X, Lee NP, Liu X, Chen S, Guo B, Yi S, Zhuang X, Chen F, Wang G, Poon RT, Fan ST, Mao M, Li Y, Li S, Wang J, Jianwang X, Jiang H, Zhang X. HIVID: an efficient method to detect HBV integration using low coverage sequencing. Genomics 2013; 102: 338-344 [PMID: 23867110]
63. Ding D, Lou X, Hua D, Yu W, Li L, Wang J, Gao F, Zhao N, Ren G, Li L, Lin B. Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach. PLoS Genet 2012; 8: e1003065 [PMID: 23236287 DOI: 10.1371/journal.pgen.1003065]
64. Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol 2010; 52: 594-604 [PMID: 20185200]
65. Garcia M, de Thé H, Tiollais P, Samarut J, Dejean A. A hepatitis B virus pre-S-retinoic acid receptor beta chimera transforms erythrocytic progenitor cells in vitro. Proc Natl Acad Sci USA 1993; 90: 89-93 [PMID: 8093562]
66. Wang J, Zindy F, Chenivesse X, Lamas E, Henglein B, Bréchot C. Modification of cyclin A expression by hepatitis B virus DNA integration in a hepatocellular carcinoma. Oncogene 1992; 7: 1653-1656 [PMID: 1321406]
67. Park IY, Sohn BH, Yu E, Suh DJ, Chung YH, Lee JH, Surzycki SJ, Lee YI. Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology 2007; 132: 1476-1494 [PMID: 17408664]
68. Rongrui L, Na H, Zongfang L, Fanpu J, Shiwen J. Epigenetic mechanism involved in the HBV/HCV-related hepatocellular carcinoma tumorigenesis. Curr Pharm Des 2014; 20: 1715-1725 [PMID: 23888939]
69. Zhao J, Wu G, Bu F, Lu B, Liang A, Cao L, Tong X, Lu X, Wu M, Guo Y. Epigenetic silence of ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region- containing protein 1 (ASPP1) and ASPP2 genes promotes tumor growth in hepatitis B virus-positive hepatocellular carcinoma. Hepatology 2010; 51: 142-153 [PMID: 20034025 DOI: 10.1002/hep.23247]
70. Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS. Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest 2007; 117: 2713-2722 [PMID: 17717605 DOI: 10.1172/JCI31457]
71. Chun E, Lee J, Cheong HS, Lee KY. Tumor eradication by hepatitis B virus X antigen-specific CD8+ T cells in xenografted nude mice. J Immunol 2003; 170: 1183-1190 [PMID: 12538674]
72. Malmassari SL, Deng Q, Fontaine H, Houitte D, Rimlinger F, Thiers V, Maillere B, Pol S, Michel ML. Impact of hepatitis B virus basic core promoter mutations on T cell response to an immunodominant HBx-derived epitope. Hepatology 2007; 45: 1199-1209 [PMID: 17465004 DOI: 10.1002/hep.21594]
73. Peng Z, Zhang Y, Gu W, Wang Z, Li D, Zhang F, Qiu G, Xie K. Integration of the hepatitis B virus X fragment in hepatocellular carcinoma and its effects on the expression of multiple molecules: a key to the cell cycle and apoptosis. Int J Oncol 2005; 26: 467-473 [PMID: 15645132]
74. Hwang GY, Lin CY, Huang LM, Wang YH, Wang JC, Hsu CT, Yang SS, Wu CC. Detection of the hepatitis B virus X protein (HBx) antigen and anti-HBx antibodies in cases of human hepatocellular carcinoma. J Clin Microbiol 2003; 41: 5598-5603 [PMID: 14662947]
75. Martín-Vílchez S, Sanz-Cameno P, Rodríguez-Muñoz Y, Majano PL, Molina-Jiménez F, López-Cabrera M, Moreno-Otero R, Lara-Pezzi E. The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells. Hepatology 2008; 47: 1872-1883 [PMID: 18449922 DOI: 10.1002/hep.22265]
76. Tralhao JG, Roudier J, Morosan S, Giannini C, Tu H, Goulenok C, Carnot F, Zavala F, Joulin V, Kremsdorf D, Bréchot C. Paracrine in vivo inhibitory effects of hepatitis B virus X protein (HBx) on liver cell proliferation: an alternative mechanism of HBx-related pathogenesis. Proc Natl Acad Sci USA 2002; 99: 6991-6996 [PMID: 12011457 DOI: 10.1073/pnas.092657699]
77. Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW. Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol 2003; 23: 5282-5292 [PMID: 12861014]
78. Wen Y, Golubkov VS, Strongin AY, Jiang W, Reed JC. Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. J Biol Chem 2008; 283: 2793-2803 [PMID: 18032378]
79. Martin-Lluesma S, Schaeffer C, Robert EI, van Breugel PC, Leupin O, Hantz O, Strubin M. 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: 1467-1476 [PMID: 18781669 DOI: 10.1002/hep.22542]
80. Kim S, Park SY, Yong H, Famulski JK, Chae S, Lee JH, Kang CM, Saya H, Chan GK, Cho H. HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint. Oncogene 2008; 27: 3457-3464 [PMID: 18193091]
81. Yu FL, Liu HJ, Lee JW, Liao MH, Shih WL. Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. J Hepatol 2005; 42: 520-527 [PMID: 15763339]
82. Ou DP, Tao YM, Tang FQ, Yang LY. The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. Int J Cancer 2007; 120: 1208-1214 [PMID: 17187364 DOI: 10.1002/ijc.22452]
83. Chung TW, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 2004; 18: 1123-1125 [PMID: 15132991 DOI: 10.1096/fj.03-1429fje]
84. Nguyen DH, Ludgate L, Hu J. Hepatitis B virus-cell interactions and pathogenesis. J Cell Physiol 2008; 216: 289-294 [PMID: 18302164 DOI: 10.1002/jcp.21416]
85. Zhang X, Zhang H, Ye L. Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med 2006; 147: 58-66 [PMID: 16459163]
86. Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Lévy L, Buendia MA, Neuveut C. The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. J Biol Chem 2007; 282: 4277-4287 [PMID: 17158882]
87. Barnabas S, Hai T, Andrisani OM. The hepatitis B virus X protein enhances the DNA binding potential and transcription efficacy of bZip transcription factors. J Biol Chem 1997; 272: 20684-20690 [PMID: 9252388]
88. Abramovitch R, Tavor E, Jacob-Hirsch J, Zeira E, Amariglio N, Pappo O, Rechavi G, Galun E, Honigman A. A pivotal role of cyclic AMP-responsive element binding protein in tumor progression. Cancer Res 2004; 64: 1338-1346 [PMID: 14973073]
89. Knoll S, Fürst K, Thomas S, Villanueva Baselga S, Stoll A, Schaefer S, Pützer BM. Dissection of cell context-dependent interactions between HBx and p53 family members in regulation of apoptosis: a role for HBV-induced HCC. Cell Cycle 2011; 10: 3554-3565 [PMID: 22030623]
90. Bergametti F, Prigent S, Luber B, Benoit A, Tiollais P, Sarasin A, Transy C. The proapoptotic effect of hepatitis B virus HBx protein correlates with its transactivation activity in stably transfected cell lines. Oncogene 1999; 18: 2860-2871 [PMID: 10362257 DOI: 10.1038/sj.onc.1202643]
91. Ahn JY, Jung EY, Kwun HJ, Lee CW, Sung YC, Jang KL. Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol 2002; 83: 2765-2772 [PMID: 12388812]
92. Mathonnet G, Lachance S, Alaoui-Jamali M, Drobetsky EA. Expression of hepatitis B virus X oncoprotein inhibits transcription-coupled nucleotide excision repair in human cells. Mutat Res 2004; 554: 305-318 [PMID: 15450428 DOI: 10.1016/j.mrfmmm.2004.05.010]
93. Lee AT, Ren J, Wong ET, Ban KH, Lee LA, Lee CG. The hepatitis B virus X protein sensitizes HepG2 cells to UV light-induced DNA damage. J Biol Chem 2005; 280: 33525-33535 [PMID: 16055925]
94. Zhang SM, Sun DC, Lou S, Bo XC, Lu Z, Qian XH, Wang SQ. HBx protein of hepatitis B virus (HBV) can form complex with mitochondrial HSP60 and HSP70. Arch Virol 2005; 150: 1579-1590 [PMID: 15789261 DOI: 10.1007/s00705-005-0521-1]
95. Yoo YG, Na TY, Seo HW, Seong JK, Park CK, Shin YK, Lee MO. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene 2008; 27: 3405-3413 [PMID: 18264140]
96. Han HK, Han CY, Cheon EP, Lee J, Kang KW. Role of hypoxia-inducible factor-alpha in hepatitis-B-virus X protein-mediated MDR1 activation. Biochem Biophys Res Commun 2007; 357: 567-573 [PMID: 17433259]
97. Sanz-Cameno P, Martín-Vílchez S, Lara-Pezzi E, Borque MJ, Salmerón J, Muñoz de Rueda P, Solís JA, López-Cabrera M, Moreno-Otero R. Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV x protein. Am J Pathol 2006; 169: 1215-1222 [PMID: 17003480]
98. Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13: 123-135 [PMID: 23344543]
99. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 2005; 19: 159-170 [PMID: 16039586]
100. Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL. Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene 2005; 24: 6617-6625 [PMID: 16007161]
101. Wang LH, Huang W, Lai MD, Su IJ. Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus pre-S2 mutants and its implication in hepatocarcinogenesis. Carcinogenesis 2012; 33: 466-472 [PMID: 22159224]
102. Xiao CX, Yang XN, Huang QW, Zhang YQ, Lin BY, Liu JJ, Liu YP, Jazag A, Guleng B, Ren JL. ECHS1 acts as a novel HBsAg-binding protein enhancing apoptosis through the mitochondrial pathway in HepG2 cells. Cancer Lett 2013; 330: 67-73 [PMID: 23178449]
103. Liu YP, Yang XN, Jazag A, Pan JS, Hu TH, Liu JJ, Guleng B, Ren JL. HBsAg inhibits the translocation of JTB into mitochondria in HepG2 cells and potentially plays a role in HCC progression. PLoS One 2012; 7: e36914 [PMID: 22615844 DOI: 10.1371/journal.pone.0036914]
104. Hsieh YH, Su IJ, Yen CJ, Tsai TF, Tsai HW, Tsai HN, Huang YJ, Chen YY, Ai YL, Kao LY, Hsieh WC, Wu HC, Huang W. Histone deacetylase inhibitor suberoylanilide hydroxamic acid suppresses the pro-oncogenic effects induced by hepatitis B virus pre-S2 mutant oncoprotein and represents a potential chemopreventive agent in high-risk chronic HBV patients. Carcinogenesis 2013; 34: 475-485 [PMID: 23172669]
105. Luan F, Liu H, Gao L, Liu J, Sun Z, Ju Y, Hou N, Guo C, Liang X, Zhang L, Sun W, Ma C. Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT. Gut 2009; 58: 1528-1537 [PMID: 19651630]
106. Ferber MJ, Montoya DP, Yu C, Aderca I, McGee A, Thorland EC, Nagorney DM, Gostout BS, Burgart LJ, Boix L, Bruix J, McMahon BJ, Cheung TH, Chung TK, Wong YF, Smith DI, Roberts LR. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene 2003; 22: 3813-3820 [PMID: 12802289 DOI: 10.1038/sj.onc.1206528]
107. Liu H, Shi W, Luan F, Xu S, Yang F, Sun W, Liu J, Ma C. Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase. Virus Genes 2010; 40: 174-182 [PMID: 20107884 DOI: 10.1007/s11262-009-0441-3]
108. Ozturk M, Arslan-Ergul A, Bagislar S, Senturk S, Yuzugullu H. Senescence and immortality in hepatocellular carcinoma. Cancer Lett 2009; 286: 103-113 [PMID: 19070423]
109. Guerrieri F, Belloni L, Pediconi N, Levrero M. Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis 2013; 33: 147-156 [PMID: 23749671 DOI: 10.1055/s-0033-1345721]
110. Zhang ZZ, Liu X, Wang DQ, Teng MK, Niu LW, Huang AL, Liang Z. Hepatitis B virus and hepatocellular carcinoma at the miRNA level. World J Gastroenterol 2011; 17: 3353-3358 [PMID: 21876625 DOI: 10.3748/wjg.v17.i28.3353]
111. Lan SH, Wu SY, Zuchini R, Lin XZ, Su IJ, Tsai TF, Lin YJ, Wu CT, Liu HS. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology 2014; 59: 505-517 [PMID: 23913306 DOI: 10.1002/hep.26659]
112. Song K, Han C, Zhang J, Lu D, Dash S, Feitelson M, Lim K, Wu T. Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology 2013; 58: 1681-1692 [PMID: 23703729 DOI: 10.1002/hep.26514]
113. Wang Y, Jiang L, Ji X, Yang B, Zhang Y, Fu XD. Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16-1 in hepatocytes. J Biol Chem 2013; 288: 18484-18493 [PMID: 23649629]
114. Wei X, Tan C, Tang C, Ren G, Xiang T, Qiu Z, Liu R, Wu Z. Epigenetic repression of miR-132 expression by the hepatitis B virus x protein in hepatitis B virus-related hepatocellular carcinoma. Cell Signal 2013; 25: 1037-1043 [PMID: 23376496]
115. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K, Ding L, Zhang H, Cheng L, Fu H, Song Y, Jiang Y, Liu J, Wang R, Du N, Ye Q. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 2013; 123: 630-645 [PMID: 23321675]
116. Xu C, Zhou W, Wang Y, Qiao L. Hepatitis B virus-induced hepatocellular carcinoma. Cancer Lett 2014; 345: 216-222 [PMID: 23981576]
117. Ayub A, Ashfaq UA, Haque A. HBV induced HCC: major risk factors from genetic to molecular level. Biomed Res Int 2013; 2013: 810461 [PMID: 23991421 DOI: 10.1155/2013/810461]
118. Bharadwaj M, Roy G, Dutta K, Misbah M, Husain M, Hussain S. Tackling hepatitis B virus-associated hepatocellular carcinoma - the future is now. Cancer Metastasis Rev 2013; 32: 229-268 [PMID: 23114844 DOI: 10.1007/s10555-012-9412-6]
119. Galuppo R, Ramaiah D, Ponte OM, Gedaly R. Molecular therapies in hepatocellular carcinoma: what can we target? Dig Dis Sci 2014; 59: 1688-1697 [PMID: 24573715 DOI: 10.1007/s10620-014-3058-x]
120. Shin JW, Chung YH. Molecular targeted therapy for hepatocellular carcinoma: current and future. World J Gastroenterol 2013; 19: 6144-6155 [PMID: 24115810 DOI: 10.3748/wjg.v19.i37.6144]