Cancer Investigation
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
Editorials: Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma Shalom Z. Hirschman To cite this article: Shalom Z. Hirschman (1991) Editorials: Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma, Cancer Investigation, 9:2, 239-240, DOI: 10.3109/07357909109044234 To link to this article: http://dx.doi.org/10.3109/07357909109044234
Published online: 11 Jun 2009.
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Date: 17 March 2016, At: 02:51
Cancer Investigation, 9(2) 239-240 (1991)
EDITORIALS
Downloaded by [ECU Libraries] at 02:51 17 March 2016
Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma Shalom Z. Hirschman, M.D. Division of Infectious Diseases The Mount Sinai School of Medicine 1 Gustave L. Levy Place, Box 1090 New Yo&, New York 10029
a direct infectious carcinogen. Subsequently many retroviruses have been discovered in tissues of animals and recently in humans (for review see Ref. 7). Directly oncogenic retroviruses cany OM genes that transform cells to a neoplastic state. Retroviruses without onc genes have been isolated from tumors and their oncogenic potential appears to involve long latent periods. HBV is the prototype of a new class of hepatotropic viruses with unusual properties (for reviews see Refs. 8 and 9). The hepatitis B virion (Dane particle) measures 42 nm in diameter and consists of an outer protein coat, HBsAg and a 27 nm nucleocapsid, hepatitis B core antigen (HBcAg). The viral core contains a partially singlestranded open circular 3.2 kb long DNA; a DNA polymerase that fills in the single-stranded region proceedings from the 3 'OH-terminus of the short (S)strand; a protein kinase that phosphorylates serine; and a protein that binds the 5 '-end of the long (L) strand of the viral DNA. Similar viruses have been detected in woodchucks, Beechey ground squirrels, and Peking ducks. In the absence of a practical cell culture system for replicating HBV, important informationon the biochemistry of HBV has been garnered through the cloning of the viral DNA in bacterial and mammalian cells. Four major open
Early observations and speculations by French and American workers (1,2), before the hepatitis A (HAV) and hepatitis B (HBV) viruses were identified, that the high incidence of primary hepatocellular carcinoma (PHC) in Africa may be related to the high prevalence of viral hepatitis and posthepatic cirrhosis have been reinforced by a steady stream of epidemiologic studies linking infection with HBV at an early age with subsequent development of PHC. The early worldwide epidemiologic data were coalesced and highlighted in a scholarly analysis by the late Dr. Wolf Szmuness (3). The most cogent epidemiologicevidence linking HBV infection and PHC was adduced by the classic studies of Beasley and colleagues in Taiwan (4). These workers showed a relative risk of 223 for PHC in carriers of hepatitis B surface antigen (HBsAg) compared with noncarriers, perhaps the strongest heretofore recognized association of an inciting factor with a neoplasia. The association of HBV infection and PHC gave new life to the viral etiology of human solid cancers,predating the subsequent association of human papilloma virus (HPV) infection and cervical carcinoma (5). The modem study of the viral etiology of cancer began with the discovery of Rous sarcoma virus (RSV) in 1911 (6) as 239
Editorial
Downloaded by [ECU Libraries] at 02:51 17 March 2016
240
reading frames have been found on the L strand. The region encoding HBsAg can be divided into two parts, gene S and pre-S. Gene C codes for HBcAg and a large region P is believed to encode the DNA polymerase. Additionally, another region, X, encodes a basic polypeptide of about 150 amino acids; expression of this protein may have some association with PHC (10). In the Dane particle a specific neick in the two strands of the DNA results in cohesive ends of 250-300 bp termed DRl and DR2. Studies with the related virus in Peking ducks by Summers and Mason showed that in the cell the viral DNA is synthesized fmm an RNA template (1 1). Indeed, the DNA polymerase appears to have properties of a reverse transcriptase (12,13). Thus HBV is related to the retroviruses and its association with cancer should not be surprising, Recently, it was found that HBV DNA may recombine with the DNA of the infecting retrovirus, HIV, in peripheral blood mononuclear cells of patients with AIDS (14). London and Buetow (Cancer Invesrigarion Vol. 6, No. 3) provide an analytic discussion of the present state of the epidemiologic and molecular data tying infection with HBV to subsequent development of PHC (15). A few points bear emphasis. The genome of HBV has not been found to contain an oncogene. Although there seems to be no clear pattern in the integration sites occupied by HBV in hepatoma cells, the viral DNA does appear to integrate through a region of the viral genome that spans the end of S, the X, and part of the C gene (16). This region contains the direct repeats and the enhancer element (17) of the viral DNA. Recently it has been shown that the enhancer sequences cooperated with the SV40 enhancer/promoter to increase gene expression when the two elements were located in the transcribed region (18). Thus the HBV enhancer may influence the expression of flanking cellular genes, includingoncogenes. HBV-DNA integration near the c-erbA cellular proto-oncogene has been described (19). The association of early HBV infection with subsequent development of PHC seems to be certain. However, more needs to be learned about the properties, and especially the mode of replication, of the virus before its mechanism of hepatic oncogenesis is understood.
REFERENCES
5.
6. 7. 8. 9.
10.
11.
12.
13.
14.
15. 16.
17. 18.
19.
Payet M, Comain R, Pene P: Le cancer primitif du foie: etude critique a propos de 240 cas. Rev Intern d'Hepatol6: 1-86, 1956. Steiner PE, Davis JNP: Cirrhosis and primary liver carcinoma in Uganda, Africa. Br J Cancer 11:523-534, 1957. Szmuness W: Hepatocellular carcinoma and hepatitis B virus: evidence for a causal association. h o g Med ViroI24:40-69,1978. Beasley RP, Lin CC, Hwang LY, Chien CS: Hepatocellular carcinoma and hepatitis B virus: a prospectivestudy of 22707 men in Taiwan. Lancet 2:1129-1133, 1981. Zoler ML: Human papilloma virus linked to cervical (and other) cancers. JAMA 249:2997-2998, 1983. Rous P: The challenge to man of the neoplastic cell. Science 157124-28, 1967. Duesberg PH: Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res 47: 1199-1220, 1987 Hirschman SZ: The hepatitis B virus and its DNA polymerase. Cell Biochem 26:47-67, 1979. Tiollais P, Purcel C, Dejean A: 'The hepatitis B virus. Nature 3 17:489-495, 1985. Moriarty AM, Alexander H, L e m r RA et al: Antibodies to peptides detect IEW hepatitis B antigen: serologicalcorrelationwith hepatocellular carcinoma. Science 227:429-433, 1985. Summers J , Mason WS: Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 9:403-415, 1982. Hirschman SZ, Vernace S , Schaffner F: DNA polymerase in preparations containing Australia antigen. Lancet 1: 1099-1 103, 1971. Will H, Salfeld J, Pfaff E et al: Putative reverse transcriptase intermediates of human hepatitis B virus in primary liver carcinomas. Science 231594496, 1986. Hischman SZ, Zucker M: Recombinant DNA related to hepatitis B and human immunodeficiency viruses in peripheral blood mononuclear cells fmm patients with AIDS. Clin Res 36:620A, 1988. London WT,Buetow K: Hepatitis B virus and primary and primary hepatocellular carcinoma. Cancer Invest 6:317-326, 1988. Dejean A, Brechot C, Tiollais P, Wain-Hobson S: Characterization of integrated hepatitis B viral DNA cloned from a human hepatoma and a hepatomaderived cell line PLC/PRF/5. Proc Natl Acad Sci (USA) 80:2505-2509, 1983. Shaul Y, R u k r WJ, Laub 0: A human hepatitis B viral enhancerelement. EMBO J 4:427430, 1985. Vannice JL, Levinson AD: Properties of the human hepatitis B v h s enhancer: position effects and cell-type mnspecificity. J Virol 62: 1305-1 3 13, 1988. DeJean A, Bougueleret L, Grzeschik KH, Tiollais P: Hepatitis B virus DNA integration in a sequence horndogus to V-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70-72, 1986.
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
Editorials: Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma Shalom Z. Hirschman To cite this article: Shalom Z. Hirschman (1991) Editorials: Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma, Cancer Investigation, 9:2, 239-240, DOI: 10.3109/07357909109044234 To link to this article: http://dx.doi.org/10.3109/07357909109044234
Published online: 11 Jun 2009.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icnv20 Download by: [ECU Libraries]
Date: 17 March 2016, At: 02:51
Cancer Investigation, 9(2) 239-240 (1991)
EDITORIALS
Downloaded by [ECU Libraries] at 02:51 17 March 2016
Hepatitis B Virus Infection and Primary Hepatocellular Carcinoma Shalom Z. Hirschman, M.D. Division of Infectious Diseases The Mount Sinai School of Medicine 1 Gustave L. Levy Place, Box 1090 New Yo&, New York 10029
a direct infectious carcinogen. Subsequently many retroviruses have been discovered in tissues of animals and recently in humans (for review see Ref. 7). Directly oncogenic retroviruses cany OM genes that transform cells to a neoplastic state. Retroviruses without onc genes have been isolated from tumors and their oncogenic potential appears to involve long latent periods. HBV is the prototype of a new class of hepatotropic viruses with unusual properties (for reviews see Refs. 8 and 9). The hepatitis B virion (Dane particle) measures 42 nm in diameter and consists of an outer protein coat, HBsAg and a 27 nm nucleocapsid, hepatitis B core antigen (HBcAg). The viral core contains a partially singlestranded open circular 3.2 kb long DNA; a DNA polymerase that fills in the single-stranded region proceedings from the 3 'OH-terminus of the short (S)strand; a protein kinase that phosphorylates serine; and a protein that binds the 5 '-end of the long (L) strand of the viral DNA. Similar viruses have been detected in woodchucks, Beechey ground squirrels, and Peking ducks. In the absence of a practical cell culture system for replicating HBV, important informationon the biochemistry of HBV has been garnered through the cloning of the viral DNA in bacterial and mammalian cells. Four major open
Early observations and speculations by French and American workers (1,2), before the hepatitis A (HAV) and hepatitis B (HBV) viruses were identified, that the high incidence of primary hepatocellular carcinoma (PHC) in Africa may be related to the high prevalence of viral hepatitis and posthepatic cirrhosis have been reinforced by a steady stream of epidemiologic studies linking infection with HBV at an early age with subsequent development of PHC. The early worldwide epidemiologic data were coalesced and highlighted in a scholarly analysis by the late Dr. Wolf Szmuness (3). The most cogent epidemiologicevidence linking HBV infection and PHC was adduced by the classic studies of Beasley and colleagues in Taiwan (4). These workers showed a relative risk of 223 for PHC in carriers of hepatitis B surface antigen (HBsAg) compared with noncarriers, perhaps the strongest heretofore recognized association of an inciting factor with a neoplasia. The association of HBV infection and PHC gave new life to the viral etiology of human solid cancers,predating the subsequent association of human papilloma virus (HPV) infection and cervical carcinoma (5). The modem study of the viral etiology of cancer began with the discovery of Rous sarcoma virus (RSV) in 1911 (6) as 239
Editorial
Downloaded by [ECU Libraries] at 02:51 17 March 2016
240
reading frames have been found on the L strand. The region encoding HBsAg can be divided into two parts, gene S and pre-S. Gene C codes for HBcAg and a large region P is believed to encode the DNA polymerase. Additionally, another region, X, encodes a basic polypeptide of about 150 amino acids; expression of this protein may have some association with PHC (10). In the Dane particle a specific neick in the two strands of the DNA results in cohesive ends of 250-300 bp termed DRl and DR2. Studies with the related virus in Peking ducks by Summers and Mason showed that in the cell the viral DNA is synthesized fmm an RNA template (1 1). Indeed, the DNA polymerase appears to have properties of a reverse transcriptase (12,13). Thus HBV is related to the retroviruses and its association with cancer should not be surprising, Recently, it was found that HBV DNA may recombine with the DNA of the infecting retrovirus, HIV, in peripheral blood mononuclear cells of patients with AIDS (14). London and Buetow (Cancer Invesrigarion Vol. 6, No. 3) provide an analytic discussion of the present state of the epidemiologic and molecular data tying infection with HBV to subsequent development of PHC (15). A few points bear emphasis. The genome of HBV has not been found to contain an oncogene. Although there seems to be no clear pattern in the integration sites occupied by HBV in hepatoma cells, the viral DNA does appear to integrate through a region of the viral genome that spans the end of S, the X, and part of the C gene (16). This region contains the direct repeats and the enhancer element (17) of the viral DNA. Recently it has been shown that the enhancer sequences cooperated with the SV40 enhancer/promoter to increase gene expression when the two elements were located in the transcribed region (18). Thus the HBV enhancer may influence the expression of flanking cellular genes, includingoncogenes. HBV-DNA integration near the c-erbA cellular proto-oncogene has been described (19). The association of early HBV infection with subsequent development of PHC seems to be certain. However, more needs to be learned about the properties, and especially the mode of replication, of the virus before its mechanism of hepatic oncogenesis is understood.
REFERENCES
5.
6. 7. 8. 9.
10.
11.
12.
13.
14.
15. 16.
17. 18.
19.
Payet M, Comain R, Pene P: Le cancer primitif du foie: etude critique a propos de 240 cas. Rev Intern d'Hepatol6: 1-86, 1956. Steiner PE, Davis JNP: Cirrhosis and primary liver carcinoma in Uganda, Africa. Br J Cancer 11:523-534, 1957. Szmuness W: Hepatocellular carcinoma and hepatitis B virus: evidence for a causal association. h o g Med ViroI24:40-69,1978. Beasley RP, Lin CC, Hwang LY, Chien CS: Hepatocellular carcinoma and hepatitis B virus: a prospectivestudy of 22707 men in Taiwan. Lancet 2:1129-1133, 1981. Zoler ML: Human papilloma virus linked to cervical (and other) cancers. JAMA 249:2997-2998, 1983. Rous P: The challenge to man of the neoplastic cell. Science 157124-28, 1967. Duesberg PH: Retroviruses as carcinogens and pathogens: expectations and reality. Cancer Res 47: 1199-1220, 1987 Hirschman SZ: The hepatitis B virus and its DNA polymerase. Cell Biochem 26:47-67, 1979. Tiollais P, Purcel C, Dejean A: 'The hepatitis B virus. Nature 3 17:489-495, 1985. Moriarty AM, Alexander H, L e m r RA et al: Antibodies to peptides detect IEW hepatitis B antigen: serologicalcorrelationwith hepatocellular carcinoma. Science 227:429-433, 1985. Summers J , Mason WS: Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 9:403-415, 1982. Hirschman SZ, Vernace S , Schaffner F: DNA polymerase in preparations containing Australia antigen. Lancet 1: 1099-1 103, 1971. Will H, Salfeld J, Pfaff E et al: Putative reverse transcriptase intermediates of human hepatitis B virus in primary liver carcinomas. Science 231594496, 1986. Hischman SZ, Zucker M: Recombinant DNA related to hepatitis B and human immunodeficiency viruses in peripheral blood mononuclear cells fmm patients with AIDS. Clin Res 36:620A, 1988. London WT,Buetow K: Hepatitis B virus and primary and primary hepatocellular carcinoma. Cancer Invest 6:317-326, 1988. Dejean A, Brechot C, Tiollais P, Wain-Hobson S: Characterization of integrated hepatitis B viral DNA cloned from a human hepatoma and a hepatomaderived cell line PLC/PRF/5. Proc Natl Acad Sci (USA) 80:2505-2509, 1983. Shaul Y, R u k r WJ, Laub 0: A human hepatitis B viral enhancerelement. EMBO J 4:427430, 1985. Vannice JL, Levinson AD: Properties of the human hepatitis B v h s enhancer: position effects and cell-type mnspecificity. J Virol 62: 1305-1 3 13, 1988. DeJean A, Bougueleret L, Grzeschik KH, Tiollais P: Hepatitis B virus DNA integration in a sequence horndogus to V-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70-72, 1986.
