• 中山醫(yī)科大學附屬第一醫(yī)院肝膽外科（廣州510080）;

目的  了解HBx基因在乙肝病毒相關性肝癌形成與發(fā)展中的分子機理。
方法 綜合國外近5年的文獻進行分析。
結果  HBx具有促進細胞惡性轉化、抑制受損DNA的修復、反式激活、抑制wtp53功能和抑制細胞凋亡等生物學功能。HBx可能通過直接致癌作用、抑制DNA的修復、抑制wtp53、干擾Fas/CD95系統(tǒng)和抑制Caspase-3 活性等分子機理，誘發(fā)肝癌形成和促進肝癌發(fā)展。
結論  HBx及其編碼的蛋白HBxAg具有廣泛的生物學功能，從多方面、多途徑促進肝癌的形成和發(fā)展。

引用本文： 李紹強 綜述 梁力建 審校. HBx在乙型肝炎病毒相關性肝癌形成與發(fā)展中的分子機理. 中國普外基礎與臨床雜志, 2001, 8(4): 279-281. doi: 復制

1. Tabor E, Gerely RJ, Voegel CL, et al. Hepatitis B virus infection and primary hepatocellular carcinoma 〔Ｊ〕. J Natl Cancer Inst, 1977; 58(5)∶1197.
2. Ritter SE, Whitten TM, Quets AT, et al. An internal domain of the hepatitis B virus X antigen is necessary for transactivating activity 〔Ｊ〕. Virology,1991; 182(2)∶841.
3. Hohne M, Schaefer S, Feilson MA, et al. Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA 〔Ｊ〕. EMBO J, 1990; 9(2)∶1137.
4. Becker SA, Lee TH, Butel JS, et al. Hepatitis B virusx protein interferes with cellular DNA repair 〔Ｊ〕. J Virol, 1998; 72(1)∶266.
5. Qadri I, Ferrari ME, Siddiqui A. The hepatitis B virus transactivator protein, HBX, interacts with singlestranded DNA(ssDNA). Biochemical characterizations of the HBxssDNA interactions 〔Ｊ〕. J Biol Chem, 1996; 271(26)∶15443.
6. Benn J, Su F, Doria M,et al. Hepatitis B virus protein induces transcription factor AP1 by activation of extracellular signalregulated and cJun Nterminal mitogenactivated protein kinases 〔Ｊ〕. J Virol, 1996; 70(8)∶4978.
7. Benn J, Schneider RJ. Hepatitis B virus HBx protein activates RasGTP complex formation and establishes a Ras, Raf, MAP kinase signalling cascade 〔Ｊ〕. Proc Natl Acad USA, 1994; 91(22)∶10350.
8. Su Q, Schoder CH, Hofmann WJ, et al. Expression of hepatitis B virus X protein in HBVinfected human livers and hepatocellular carcinoma 〔Ｊ〕. Hepatology, 1998; 27(4)∶1109.
9. Nomura T, Lin Y, Dorjsuren D, et al. Human hepatitis B virus X protein is detectable in nuclei of transfected cells, and is active for transactivation 〔Ｊ〕. Biochim Biophys Acta, 1999; 1453(3)∶330.
10. Koike K, Moriya K, Iino S, et al. Highlevel of expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice 〔Ｊ〕. Hepatology, 1994; 19(4)∶810.
11. Leveillard T, Andera I, Bissonnette N, et al. Functional interactions between p53 and the TFIIH complex are affected by tumorassociated mutations 〔Ｊ〕. EMBO J, 1996; 15(7)∶1615.
12. Wang XW, Gibson MK, Vermeulen W, et al. The XPB and XPD DNA helicases are components of the p53mediated apoptosis pathway 〔Ｊ〕. Genes Dev, 1996; 10(10)∶1219.
13. Wu X, Levine AJ. p53 and E2 F1 cooperate to mediate apoptosis 〔Ｊ〕.Proc Natl Acaid Sci USA, 1994; 91(9)∶23602.
14. Dulic V, Kaufmann WK, Wilson SJ, et al. p53dependent inhibition of cyclindependent kinase activities in human fibroblasts during radiationinduced G1 arrest 〔Ｊ〕. Cell, 1994; 76(6)∶1013.
15. Harris C. p53: At the crossroads of molecular carcinogenesis and risk assessment 〔Ｊ〕. Science, 1993; 262(5142)∶1980.
16. Oda T, Tsuda H, Scarpa A,et al. p53 gene mutation spectrum in hepatocellular carcinoma 〔Ｊ〕. Cancer Res, 1992; 52(22)∶6358.
17. Greenblatt M, Bennett WP, Hollstein M, et al. Mutation in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis 〔Ｊ〕. Drug Metab Rev, 1994; 26(1-2)∶4855.
18. Wang XW, Gibson MK, Vermeulen W, et al. Abrogation of p53induced apoptosis by the hepatitis B virus X gene 〔Ｊ〕. Cancer Res, 1995; 55(24)∶6012.
19. Lin Y, Nomura T, Yamashita T, et al. The transactivation and p53interacting function of hepatitis B virus X protein are mutually interfering but distnct 〔Ｊ〕. Cancer Res, 1997; 57(22)∶5137.
20. Wang XW, Forrester K, Yeh H, et al. Hepatitis B virus X protein inhibits p53 sequencespecific DNA binding, transcriptional activity, and association with transcription factor ERCC3 〔Ｊ〕. Proc Acad Sci USA, 1994; 91(6)∶2230.
21. Elmore LW, Hancock AR, Chang SF, et al. Hepatitis B virus X protein and p53 tumor suppressor interaction in the modulation o apoptosis 〔Ｊ〕. Proc Acad Sci USA, 1997; 94(26)∶14707.
22. Griffith TS, Ferguson TA. The role of FasLinduced apoptosis in immune privilege 〔Ｊ〕. Immunology Today, 1997; 18(5)∶240.
23. Nagao M, Nakajima Y, Hisanaga M, et al. The alteration of Fas receptor and ligand system in hepatocellular carcinoma: How do hepatoma cells escape from the host immune surveillance in vivo 〔Ｊ〕? Hepatology, 1999; 30(2)∶413.
24. Muller M, Wilder S, Bannasch D, et al. p53 activates CD95(APO1/Fas) gene in response to DNA damage by anticancer drugs 〔Ｊ〕. J Exp Med 1998; 188(11)∶2033.
25. Shin EC, Shin JS, Park JH, et al . Expression of Fas ligand in human hepatoma cell lines: role of hepatitis B virus X (HBX) in induction of Fas ligand 〔Ｊ〕. Int J Cancer, 1999;82(4)∶587.
26. Takada S, Kida M, Fukutomi H, et al . Interaction of hepatitis B virus X protein with a serine protease tryptase TL2 as an inhibitor 〔Ｊ〕. Oncogene, 1994; 9(2)∶341.
27. Gottlob K, Fulco M, Levrero M, et al . The hepatitis B virus HBx protein inhibits capcase 3 activity 〔Ｊ〕. J Biol Chem, 1998; 273(50)∶33347.
  1. 1. Tabor E, Gerely RJ, Voegel CL, et al. Hepatitis B virus infection and primary hepatocellular carcinoma 〔Ｊ〕. J Natl Cancer Inst, 1977; 58(5)∶1197.
  2. 2. Ritter SE, Whitten TM, Quets AT, et al. An internal domain of the hepatitis B virus X antigen is necessary for transactivating activity 〔Ｊ〕. Virology,1991; 182(2)∶841.
  3. 3. Hohne M, Schaefer S, Feilson MA, et al. Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA 〔Ｊ〕. EMBO J, 1990; 9(2)∶1137.
  4. 4. Becker SA, Lee TH, Butel JS, et al. Hepatitis B virusx protein interferes with cellular DNA repair 〔Ｊ〕. J Virol, 1998; 72(1)∶266.
  5. 5. Qadri I, Ferrari ME, Siddiqui A. The hepatitis B virus transactivator protein, HBX, interacts with singlestranded DNA(ssDNA). Biochemical characterizations of the HBxssDNA interactions 〔Ｊ〕. J Biol Chem, 1996; 271(26)∶15443.
  6. 6. Benn J, Su F, Doria M,et al. Hepatitis B virus protein induces transcription factor AP1 by activation of extracellular signalregulated and cJun Nterminal mitogenactivated protein kinases 〔Ｊ〕. J Virol, 1996; 70(8)∶4978.
  7. 7. Benn J, Schneider RJ. Hepatitis B virus HBx protein activates RasGTP complex formation and establishes a Ras, Raf, MAP kinase signalling cascade 〔Ｊ〕. Proc Natl Acad USA, 1994; 91(22)∶10350.
  8. 8. Su Q, Schoder CH, Hofmann WJ, et al. Expression of hepatitis B virus X protein in HBVinfected human livers and hepatocellular carcinoma 〔Ｊ〕. Hepatology, 1998; 27(4)∶1109.
  9. 9. Nomura T, Lin Y, Dorjsuren D, et al. Human hepatitis B virus X protein is detectable in nuclei of transfected cells, and is active for transactivation 〔Ｊ〕. Biochim Biophys Acta, 1999; 1453(3)∶330.
  10. 10. Koike K, Moriya K, Iino S, et al. Highlevel of expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice 〔Ｊ〕. Hepatology, 1994; 19(4)∶810.
  11. 11. Leveillard T, Andera I, Bissonnette N, et al. Functional interactions between p53 and the TFIIH complex are affected by tumorassociated mutations 〔Ｊ〕. EMBO J, 1996; 15(7)∶1615.
  12. 12. Wang XW, Gibson MK, Vermeulen W, et al. The XPB and XPD DNA helicases are components of the p53mediated apoptosis pathway 〔Ｊ〕. Genes Dev, 1996; 10(10)∶1219.
  13. 13. Wu X, Levine AJ. p53 and E2 F1 cooperate to mediate apoptosis 〔Ｊ〕.Proc Natl Acaid Sci USA, 1994; 91(9)∶23602.
  14. 14. Dulic V, Kaufmann WK, Wilson SJ, et al. p53dependent inhibition of cyclindependent kinase activities in human fibroblasts during radiationinduced G1 arrest 〔Ｊ〕. Cell, 1994; 76(6)∶1013.
  15. 15. Harris C. p53: At the crossroads of molecular carcinogenesis and risk assessment 〔Ｊ〕. Science, 1993; 262(5142)∶1980.
  16. 16. Oda T, Tsuda H, Scarpa A,et al. p53 gene mutation spectrum in hepatocellular carcinoma 〔Ｊ〕. Cancer Res, 1992; 52(22)∶6358.
  17. 17. Greenblatt M, Bennett WP, Hollstein M, et al. Mutation in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis 〔Ｊ〕. Drug Metab Rev, 1994; 26(1-2)∶4855.
  18. 18. Wang XW, Gibson MK, Vermeulen W, et al. Abrogation of p53induced apoptosis by the hepatitis B virus X gene 〔Ｊ〕. Cancer Res, 1995; 55(24)∶6012.
  19. 19. Lin Y, Nomura T, Yamashita T, et al. The transactivation and p53interacting function of hepatitis B virus X protein are mutually interfering but distnct 〔Ｊ〕. Cancer Res, 1997; 57(22)∶5137.
  20. 20. Wang XW, Forrester K, Yeh H, et al. Hepatitis B virus X protein inhibits p53 sequencespecific DNA binding, transcriptional activity, and association with transcription factor ERCC3 〔Ｊ〕. Proc Acad Sci USA, 1994; 91(6)∶2230.
  21. 21. Elmore LW, Hancock AR, Chang SF, et al. Hepatitis B virus X protein and p53 tumor suppressor interaction in the modulation o apoptosis 〔Ｊ〕. Proc Acad Sci USA, 1997; 94(26)∶14707.
  22. 22. Griffith TS, Ferguson TA. The role of FasLinduced apoptosis in immune privilege 〔Ｊ〕. Immunology Today, 1997; 18(5)∶240.
  23. 23. Nagao M, Nakajima Y, Hisanaga M, et al. The alteration of Fas receptor and ligand system in hepatocellular carcinoma: How do hepatoma cells escape from the host immune surveillance in vivo 〔Ｊ〕? Hepatology, 1999; 30(2)∶413.
  24. 24. Muller M, Wilder S, Bannasch D, et al. p53 activates CD95(APO1/Fas) gene in response to DNA damage by anticancer drugs 〔Ｊ〕. J Exp Med 1998; 188(11)∶2033.
  25. 25. Shin EC, Shin JS, Park JH, et al . Expression of Fas ligand in human hepatoma cell lines: role of hepatitis B virus X (HBX) in induction of Fas ligand 〔Ｊ〕. Int J Cancer, 1999;82(4)∶587.
  26. 26. Takada S, Kida M, Fukutomi H, et al . Interaction of hepatitis B virus X protein with a serine protease tryptase TL2 as an inhibitor 〔Ｊ〕. Oncogene, 1994; 9(2)∶341.
  27. 27. Gottlob K, Fulco M, Levrero M, et al . The hepatitis B virus HBx protein inhibits capcase 3 activity 〔Ｊ〕. J Biol Chem, 1998; 273(50)∶33347.