Abstract
Alexander and co-workers1 have developed a tissue culture cell line (PLC/PRF/5) from a primary hepatocellular carcinoma of a Mozambican male with a positive serum for hepatitis B virus surface antigen (HBsAg). This cell line produces and secretes HBsAg but no other known viral protein1–3. PLC/PRF/5 therefore contains at least part of the hepatitis B virus (HBV) genome in functional form. The 42-nm, spherical Dane particle in human serum is thought to represent the complete infectious agent of HBV4. The core of this particle contains circular double-stranded DNA in which one strand is ‘nicked’ (complete but not covalently closed) and the other strand is incomplete (lacking 15–45% of its sequence complement)4,5. Four proteins have been associated with the HBsAg, core antigen (HBcAg), e antigen and a viral DNA polymerase4. Several groups have now cloned Dane particle DNA in Escherichia coli6–10, and both restriction maps and a complete DNA sequence have been determined. Various studies suggest that there is sequence heterogeneity in Dane particle DNA isolated from patients expressing the same or different viral subtypes, as well as sequence variation in different clones of Dane particle DNA obtained from a given individual10,11. Other studies12,13 have reported HBV DNA sequences in DNA from liver cancer tissue. In none of these cases was viral DNA reported to be integrated into the host cell genome. With the improvement in techniques for characterizing viral DNA molecules, we have begun to analyse HBV genes and their expression in the PLC/PRF/5 cell line by molecular hybridization of cellular DNA and RNA to cloned 32P-labelled plasmid HBV DNA. We now present evidence in PLC/PRF/5 cells for integration of HBV DNA into the host genome and expression of three RNA molecules containing HBV-specific sequences. These findings are consistent with observations in several animal virus models in which integrated viral DNA is found during oncogenic transformation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Macnab, M., Alexander, J. J., Lecatsas, G., Bey, E. M. & Urbanowicz, J. M. Br. J. Cancer 34, 509–515 (1976).
Marion, P. L., Salazar, F. H., Alexander, J. J. & Robinson, W. S. J. Virol. 32, 796–802 (1979).
Skelly, J., Copeland, J.A., Howard, C.R. & Zuckerman, A.J. Nature 282, 617–618 (1979).
Robinson, W.S. A. Rev. Microbiol. 31, 357–377 (1977).
Summers, J., O'Connell, A. & Millman, I. Proc. natn. Acad. Sci. U.S.A. 72, 4597–4601 (1975).
Burrell, C.J., Mackay, P., Greenaway, P.J., Hofschneider, P.H. & Murray, K. Nature 279, 43–47 (1979).
Charnay, P., Pourcel, C., Louise, A., Fritsch, A. & Tiollais, P. Proc. natn. Acad. Sci. U.S.A. 76, 2222–2226 (1979).
Sninsky, J.J., Siddiqui, A., Robinson, W. & Cohen, S. N. Nature 279, 346–348 (1979).
Valenzuela, P. et al. Nature 280, 815–819 (1979).
Pasek, M. et al. Nature 282, 575–579 (1979).
Siddiqui, A., Sattler, F. & Robinson, W. S. Proc. natn. Acad. Sci. U.S.A. 76, 4664–4668 (1979).
Lutwick, L. I. & Robinson, W. S. J. Virol. 21, 96–104 (1977).
Summers, J. et al. J. med. Virol. 2, 207–214 (1978).
Southern, E. M. J. molec. Biol. 98, 503–517 (1975).
Alwine, J. C., Kemp, D. J. & Stark, G. R. Proc. natn. Acad. Sci. U.S.A. 74, 5350–5354 (1977).
Tooze, J. Molecular Biology of Tumor Viruses Pt 2 (Cold Spring Harbor Laboratory, New York, 1979).
Szmuness, W. Prog. med. Virol. 24, 40–69 (1978).
Alexander, J., Macnab, G. & Sanders, R. Perspectives Virol. 10, 103–120 (1978).
Desmyter, J., Roy, M. B., Bradburne, A. F. & Alexander, J. J. in Viral Hepatitis (eds Vyas, G. N., Cohen, S. N. & Schmid, R.) Ch. 44 (Franklin Institute Press, Philadelphia, 1978).
Varmus, H. E., Guntaka, R. V., Deng, C. T. & Bishop, J. M. Cold Spring Harb. Symp. quant. Biol. 39, 987–996 (1974).
Steffen, D. & Weinberg, R. A. Cell 15, 1003–1010 (1978).
Botchan, M., Topp, W. & Sambrook, J. Cell 9, 269–287 (1976).
Flint, J. Cell 10, 156–166 (1977).
Lindberg, U. & Darnell, J. E. Proc. natn. Acad. Sci. U.S.A. 65, 1089–1096 (1970).
Tonegawa, S., Walter, G., Bernardini, A. & Dulbecco, R. Cold Spring Harb. Sym. quant. Biol. 35, 823–831 (1970).
Acheson, N. H., Buetti, E., Scherrer, K. & Weil, R. Proc. natn. Acad. Sci. U.S.A. 68, 2231–2235 (1971).
Rozenblatt, S. & Winocour, E. Virology 50, 558–566 (1972).
Wall, R. & Darnell, J. E. in The Biology of DNA Tumor Viruses (ed. Schiminovich, S.) 191–199 (Plenum, New York, 1976).
Marion et al. J. Virol. 33, 795–806 (1980).
Cummmings, I. W. et al. Proc. natn. Acad. Sci. U.S.A. 77, 1842–1846 (1980).
Dingman, C. W. & Peacock, A. C. Biochemistry 7, 659–667 (1968).
Rigby, P. W., Dickmann, M. A., Rhodes, C. & Berg, P. J. molec. Biol. 113, 237–251 (1977).
Innis, M. & Miller, D. J. biol. Chem. 254, 9148–9154 (1979).
McMaster, G. K. & Carmichael, G. G. Proc. natn. Acad. Sci. U.S.A. 74, 4835–4838 (1977).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chakraborty, P., Ruiz-Opazo, N., Shouval, D. et al. Identification of integrated hepatitis B virus DNA and expression of viral RNA in an HBsAg-producing human hepatocellular carcinoma cell line. Nature 286, 531–533 (1980). https://doi.org/10.1038/286531a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/286531a0
This article is cited by
-
Genetic and epigenetic alterations in hepatitis B virus-associated hepatocellular carcinoma
Virologica Sinica (2015)
-
Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma
Nature Genetics (2012)
-
From mosquito to man: Identification of a novel protein kinase, HsHPK, which is highly expressed in human hepatoma tissues
Journal of Biomedical Science (1998)
-
Rapid growth of hepatocellular carcinoma after or during interferon treatment for chronic hepatitis C: Report of three cases
Surgery Today (1996)
-
Hepatitis C virus replication is associated with expression of transforming growth factor-α and insulin-like growth factor-II in cirrhotic livers
Digestive Diseases and Sciences (1996)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.