O papel da proteína HBx no desenvolvimento do hepatocarcinoma celular
Conteúdo do artigo principal
Resumo
A infecção crônica causada pelo vírus da hepatite B, conhecido como HBV, está fortemente associada ao aparecimento do hepatocarcinoma (HCC), um tumor maligno com mau prognóstico, cujo desenvolvimento é relacionado à proteína X do referido vírus. A integração do DNA viral, que codifica a proteína HBx no genoma da célula hospedeira, aumenta a expressão dessa proteína e, conseqüentemente, aumenta sua interação com os genes e proteínas reguladoras da célula hospedeira. A proteína HBx desenvolve uma variedade de funções biológicas, como transativação genética, interação com a proteína P53, interferência no reparo do DNA, repressão de proteólises fisiológicas, modulação da proliferação celular e apoptose e indução da migração de células malignas, apresentando também importante papel no desenvolvimento do HCC associado à infecção pelo HBV. Entretanto, diferentes níveis de expressão do gene da HBx em hepatócitos determinam resultados diversos e até opostos em relação ao ciclo celular e apoptose. Através de inúmeros mecanismos, a proteína HBx é capaz de coordenar o balanço entre proliferação celular e morte celular programada, o que é determinante no desenvolvimento do HCC, principalmente em pacientes com infecção crônica por HBV.
Downloads
Detalhes do artigo
Referências
Ministério da Saúde. Câncer de fígado. [2 telas]. Disponível em URL: http://www.inca.gov.br/conteudo_view.asp?id=330. Acessado em: 23 de janeiro de 2005.
Lupberger J, Hildt E. Hepatitis B virus-induced oncogenesis. World J Gastroenterol 2007;13(1):74-81.
Stacey KO, Kathleen CL, Michelle CB. Hepatitis B viral transactivator HBx alleviates P53-mediated repression of alfafetoprotein gene expression. J Biol Chem 2000;275(36):27806-14.
Jorge SG. Hepatite B. 2003. [2 telas]. Disponível em URL: http://www.hepcentro.com.br/hepatite_b.htm. Acessado em: 14 de junho de 2005.
Eli B, Richard C, Geoffrey S. Imunologia. 4a ed. Rio de Janeiro, Brasil: Guanabara Koogan; 2002. p. 447-54.
Guo SP, Wang WL, Zhai YL. Expression of nuclear factor-KB in hepatocellular carcinoma and its relation with the x protein of hepatitis B virus. World J Gastroentero 2001;7(3):340-34.
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer 2001;37(Suppl 8): S4-S66 . http://dx.doi.org/10.1016/S0959-8049(01)00267-2
Bruss V. Hepatitis B virus morphogenesis. World J Gastroenterol 2007;13(1):65-73.
Robbins SL, Kumar V, Contran RS. Patologia estrutural e funcional. 7a ed. Rio de Janeiro, Brasil: Guanabara Koogan; 2005. p. 934-6.
Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36:1206-13. http://dx.doi.org/10.1053/jhep.2002.36780
Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, Chen DS, Chen CJ. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 2002;347:168-74. http://dx.doi.org/10.1056/NEJMoa013215
Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678-86. http://dx.doi.org/10.1053/j.gastro.2005.11.016
Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular characteristics. J Gastroenterol Hepatol 2002;17:643-50. http://dx.doi.org/10.1046/j.1440-1746.2002.02737.x
Sugauchi F, Kumada H, Acharya SA, Shrestha SM, Gamutan MT, Khan M, Gish RG, Tanaka Y, Kato T, Orito E, Ueda R, Miyakawa Y, Mizokami M. Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. J Gen Virol 2004;85:811-20. http://dx.doi.org/10.1099/vir.0.79811-0
Hermes JG, Benjamin B. Nitric oxide disrupts H2O2 – dependent activation of nuclear Factor kB. J Biol Chem 2001.
Lee AT, Lee CG. Oncogenesis and transforming viruses: the hepatitis B virus and hepatocellularcarcinoma – the etiopathogenic link. Front Biosci 20071;12:234-45.
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(2):58-66. http://dx.doi.org/10.1016/j.lab.2005.10.003
Livezey KW, Negorev D, Simon D. Increased chromosome alterations and micronuclei formation in human HepG2 cells transfected with the hepatitis B virus HBX gene. Mutat Res 2002;505(1-2):63-74. http://dx.doi.org/10.1016/S0027-5107(02)00140-9
Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001;12(2-3):189-205. http://dx.doi.org/10.1016/S1359-6101(00)00034-4
Su F, Schneider RJ. Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. J Virol 1996;70(7):4558-66.
Wang T, Wu Y, Wu MC, Guan XY, Yin ZF. Activating mechanism of transcriptor NF-KappaB regulated by hepatitis B virus X protein in hepatocellular carcinoma. World J Gastroenterol 2004;10(3):356-60.
Lee YI, Kang-Parrk S, Do SI, Lee YI. The hepatitis B virus-x protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. Hepatol 2001;34(3):409-15.
Chang ZS, Zeng LB, Chang CS, Qing WW. Aggregate formation of hepatitis B virus X protein affects cell cycle and apoptosis. World J Gastroenterol 2003;9:1521-4.
Li D, Chen X, Zhang W. The inhibition of apoptosis of hepatoma cells induced by HBx is mediated by up-regulation of surviving expression. Jhuazhong Univ Sci Tecnolog Med Sci 2003;23(4):383-6.http://dx.doi.org/10.1007/BF02829424
Elmore LW, Hancock AR, Chang SF, Wang XW, Chang S, Callahan CP, Geller DA, Will H, Harris CC. Hepatitis B virus X protein and P53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci USA 1997;94(26):14707-12. http://dx.doi.org/10.1073/pnas.94.26.14707
Tae WC, Young CL, Jeong HK, Cheorl HK. Hepatitis B virus X protein modulates the expression of PTEN by inhibiting the function of P53, a transcriptional activator in liver cells. Cancer Res 2003;63:3453-8.
Kang-Park S, Im JH, Lee JH, Lee YI. PTEN modulates hepatitis B virus-X protein induced survival signaling in Chang liver cells. Virus Res 2006;122(1-2):53-60. http://dx.doi.org/10.1016/j.virusres.2006.06.010
Lee YI, Hwang JM, Im JH, Kim NS, 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(15):15460-71. http://dx.doi.org/10.1074/jbc.M309280200
Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, Brechot C, Harris CC. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology 2002;181-182:43-7. http://dx.doi.org/10.1016/S0300-483X(02)00253-6
Abbas AK, Lichtman AH. Imunologia celular e molecular. 5a ed. Rio de Janeiro, Brasil, Elsevier; 2005. p. 191-192;413.
Chan CF, Yau TO, Jin DT, Wong CH, Fan ST, Ng IO. Evaluation of nuclear factor Kappa-B, urokinase-type plasminogen activator and HBx and their clinicopathological significance in hepatocellular carcinoma. Cancer Res 2004;10(12):4140-8.
Feng Z, He R, Lu Z, Ling Y. Expression of ras oncogene P21 product and proliferating cell nuclear antigen in liver cirrhosis and the correlation with liver cell dysplasia. Zhonghua Gan Zang Bing Za Zhi 2000;8(6):343-5.
Su F, Schneider RJ. Hepatitis B virus HBx protein Activates transcriptor facto NF-KB by acting on multiple cytoplasmic inhibitors of Rel related proteins. J Virol 1996;70(7):4558-6.
Birbach A, Gold P, Binder BR, Hofer E, Martin RSchimid SA. Signaling molecules of the NF-KB pathway shuttle constitutively between cytoplasm and nucleus. J Biol Chem 2002;277(13):10842-51. http://dx.doi.org/10.1074/jbc.M112475200
Chirillo P, Falco M, Puri PL, Artini M, Balsano C, Levrero M, Natoli G. Hepatitis B virus PX activates NF-KB-Dependent transcription through a Raf-Independent pathway. J Virol 1996;70(1):641-6.
Guo SP, Wang WL, Zhai YQ, Zhao YL. Expression of nuclear factor-kappa B in hepatocellular carcinoma and its relation with the X protein of hepatitis B virus. World J Gastroenterol 2001;7(3):340-4.
Zhang JL, Zhao WG, Wu KL, Wang K, Zhang X, Gu CF, Li Y, Zhu Y, Wu JG. Human hepatitis B virus X protein promotes cell proliferation and inhibits cell apoptosis trough interacting with a serine protease hepsin. Arch Virol 2005;150(4):721-41. Epub 2004 Dez 21.
Becker SA, Lee TH, Butel JS, Slogle BL. Hepatitis virus X protein Interferes with cellular DNA repair. J Virol 1998;72(1):266-72. [Epub ahead of print].
Young SY, Sung GP, Sung MB, Young GK, Guhung J. Hepatitis B virus X protein induces TNF-α expression via downregulation of selenoprotein P in human hepatoma cell line, HepG2. BBA 2003;1638(2003):249-56.
Lee MO, Kang HJ, Cho H, Shin EC, Park JH, Kim SJ. Hepatitis B virus X protein induced expression of the Nur77 gene. Bio Chem Biophys Res Commum 1991;288(5):1162-8. http://dx.doi.org/10.1006/bbrc.2001.5910
Yoo YG, Lee MO. Hepatitis B virus X protein induces expression of Fas ligand gene through activity of early growth response factor. J Biol Chem 2004;279(35):36242-9. http://dx.doi.org/10.1074/jbc.M401290200
Lee MO, Choi YH, Shin EC, Kang HJ, Kim YM, Jeong SY, Seong JK, Yu DY, Cho H, Park JH, Kim SJ. Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection. J Hepatol 2002;37(3):380-6. http://dx.doi.org/10.1016/S0168-8278(02)00181-2
Enrique LP, Gómez GMV, Gálvez BG, Mira E, I-iquez MA, Fresno M, Martinez AC, Arroyo AG, Cabrera ML. The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cycloxygenase-2 expression. J Clin Invest 2002;110(12):1831-8. http://dx.doi.org/10.1172/JCI200215887
Lara-Pezzi E, Roche S, Andrisani OM, Sanchez-Madrid F, Lopez-Cabrera M. The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene 2001;20(26):3323-31. http://dx.doi.org/10.1038/sj.onc.1204451
Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzalo M, Carretero M, Moreno-Otero R, Sanchez-Madrid F, Lopez-Cabrera M. Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. Hepatol 2001;34(3):409-15. http://dx.doi.org/10.1016/S0168-8278(00)00090-8
Chung YG, Lee YC, Kim CH. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3k0AKT pathways: involvement of invasive potential. FASEB J 2004;18(10):1123-35.
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(6):1208-14. http://dx.doi.org/10.1002/ijc.22452
Michel B, Robyn P, Robert JS. Tumor necrosis factor alpha inhibition of hepatitis B virus replication involves disruption of capsid integrity through activation of NF-kB. J Virology 2003;77(7):4033-42. http://dx.doi.org/10.1128/JVI.77.7.4033-4042.2003
Huo TI, Wang XW, Forgues M, Wu CG, Spillare EA, Giannini C, Brechot C, Harris CC. Hepatitis B X virus mutants derived from human hepatocellular carcinoma retain the ability to abrogate P53-induced apoptosis. Oncogene 2001;20(28):3620-8. http://dx.doi.org/10.1038/sj.onc.1204495
Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C. Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogen 1999;18(34):4848-59. http://dx.doi.org/10.1038/sj.onc.1202867
Wang JC, Hsu SL, Hwang GY. Inhibition of tumorigenicity of the hepatitis B virus X gene in Chang liver cell line. Virus Res 2004;102(2):133-9. http://dx.doi.org/10.1016/j.virusres.2004.01.023
Tu H, Bonura C, Giannini C, Mouly H, Soussan P, Kew M, Paterlini-Brechot C, Kremsdorf D. Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res 2001;61(21):7803-10.
Cheng AS, Wong N, Tse AM, Chan KY, Chan KK, Sung JJ, Chan HL. RNA interference targeting HBx suppresses tumor growth and enhances cisplatin chemosensitivity in human hepatocellular carcinoma. Cancer Lett. 2007 Feb 10. [Epub ahead of print] http://dx.doi.org/10.1016/j.canlet.2007.01.004
Chan DW, Ng IO. Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. J Pathol 2006;208(3):372-80. http://dx.doi.org/10.1002/path.1901
Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 1993;361:742-5. http://dx.doi.org/10.1038/361742a0
Friedrich B, Wollersheim M, Brandenburg B, Foerste R, Will H, Hildt E. Induction of anti-proliferative mechanisms in hepatitis B virus producing cells. J Hepatol 2005;43:696-703. http://dx.doi.org/10.1016/j.jhep.2005.02.026
Kekule AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R. The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 1990;343:457-61. http://dx.doi.org/10.1038/343457a0