Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1988 Sep;62(9):3422–3430. doi: 10.1128/jvi.62.9.3422-3430.1988

Insulinlike growth factor II expression and oval cell proliferation associated with hepatocarcinogenesis in woodchuck hepatitis virus carriers.

X X Fu 1, C Y Su 1, Y Lee 1, R Hintz 1, L Biempica 1, R Snyder 1, C E Rogler 1
PMCID: PMC253466  PMID: 2457114

Abstract

Insulinlike growth factor II (IGF-II) is a highly mitogenic fetal growth factor suspected of regulating the growth of a wide spectrum of tissues via an autocrine or paracrine mode of action or both. High steady-state levels of IGF-II RNA were detected in 45% of hepatocellular carcinomas (HCCs) arising from woodchuck livers with persistent woodchuck hepatitis virus (WHV) infection. Analysis of WHV RNA in the same HCCs revealed that HCCs with high levels of IGF-II RNA contained low or undetectable levels of WHV RNA and HCCs with low levels of IGF-II RNA contained high levels of WHV RNA. Integrated WHV DNA was present in HCCs from both groups, but viral DNA replicating forms were present, predominantly in HCCs with low levels of IGF-II. Several IGF-II RNAs, the most prominent of which were poly(A) species of approximately 3.75 and 1.1 to 1.3 kilobases, were detected only in precancerous nodules and HCCs. Levels of IGF-II were elevated two- to three-fold in the serum of woodchucks with chronic active hepatitis preceding the occurrence of HCC. Proliferation of a population of oval cells, which arise from portal tract regions in the liver, preceded the development of HCC and was a prominent feature of livers from which tumors with high levels of IGF-II occurred. The HCCs tended to have distinct histological features according to their growth factor status. Tumors with low levels of IGF-II were generally highly differentiated acinar-trabecular HCCs, whereas tumors with high levels of IGF-II were more anaplastic, with regions of fibrosis and fatty accumulation. A model to relate the pathology of WHV infection to oval cell proliferation and IGF-II expression in the development of these heterogeneous HCCs is presented.

Full text

PDF
3422

Images in this article

3424Image
on p.3424
3424Image
on p.3424
3426Image
on p.3426
3427Image
on p.3427
3428Image
on p.3428

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bell G. I., Merryweather J. P., Sanchez-Pescador R., Stempien M. M., Priestley L., Scott J., Rall L. B. Sequence of a cDNA clone encoding human preproinsulin-like growth factor II. 1984 Aug 30-Sep 5Nature. 310(5980):775–777. doi: 10.1038/310775a0. [DOI] [PubMed] [Google Scholar]
  3. Blazar B. A., Sutton L. M., Strome M. Self-stimulating growth factor production by B-cell lines derived from Burkitt's lymphomas and other lines transformed in vitro by Epstein-Barr virus. Cancer Res. 1983 Oct;43(10):4562–4568. [PubMed] [Google Scholar]
  4. Braun L., Goyette M., Yaswen P., Thompson N. L., Fausto N. Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats. Cancer Res. 1987 Aug 1;47(15):4116–4124. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Dulak N. C., Temin H. M. Multiplication-stimulating activity for chicken embryo fibroblasts from rat liver cell conditioned medium: a family of small polypeptides. J Cell Physiol. 1973 Apr;81(2):161–170. doi: 10.1002/jcp.1040810205. [DOI] [PubMed] [Google Scholar]
  7. Evarts R. P., Nagy P., Marsden E., Thorgeirsson S. S. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987 Nov;8(11):1737–1740. doi: 10.1093/carcin/8.11.1737. [DOI] [PubMed] [Google Scholar]
  8. FARBER E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956 Feb;16(2):142–148. [PubMed] [Google Scholar]
  9. Farber E. Cellular biochemistry of the stepwise development of cancer with chemicals: G. H. A. Clowes memorial lecture. Cancer Res. 1984 Dec;44(12 Pt 1):5463–5474. [PubMed] [Google Scholar]
  10. Frunzio R., Chiariotti L., Brown A. L., Graham D. E., Rechler M. M., Bruni C. B. Structure and expression of the rat insulin-like growth factor II (rIGF-II) gene. rIGF-II RNAs are transcribed from two promoters. J Biol Chem. 1986 Dec 25;261(36):17138–17149. [PubMed] [Google Scholar]
  11. Ganem D., Varmus H. E. The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987;56:651–693. doi: 10.1146/annurev.bi.56.070187.003251. [DOI] [PubMed] [Google Scholar]
  12. Greene W. C., Leonard W. J., Wano Y., Svetlik P. B., Peffer N. J., Sodroski J. G., Rosen C. A., Goh W. C., Haseltine W. A. Trans-activator gene of HTLV-II induces IL-2 receptor and IL-2 cellular gene expression. Science. 1986 May 16;232(4752):877–880. doi: 10.1126/science.3010456. [DOI] [PubMed] [Google Scholar]
  13. Heard J. M., Fichelson S., Sola B., Martial M. A., Varet B., Levy J. P. Multistep virus-induced leukemogenesis in vitro: description of a model specifying three steps within the myeloblastic malignant process. Mol Cell Biol. 1984 Jan;4(1):216–220. doi: 10.1128/mcb.4.1.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hino O., Shows T. B., Rogler C. E. Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8338–8342. doi: 10.1073/pnas.83.21.8338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hixson D. C., Allison J. P. Monoclonal antibodies recognizing oval cells induced in the liver of rats by N-2-fluorenylacetamide or ethionine in a choline-deficient diet. Cancer Res. 1985 Aug;45(8):3750–3760. [PubMed] [Google Scholar]
  16. Irminger J. C., Rosen K. M., Humbel R. E., Villa-Komaroff L. Tissue-specific expression of insulin-like growth factor II mRNAs with distinct 5' untranslated regions. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6330–6334. doi: 10.1073/pnas.84.18.6330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee P. D., Hodges D., Hintz R. L., Wyche J. H., Rosenfeld R. G. Identification of receptors for insulin-like growth factor II in two insulin-like growth factor II producing cell lines. Biochem Biophys Res Commun. 1986 Jan 29;134(2):595–600. doi: 10.1016/s0006-291x(86)80461-2. [DOI] [PubMed] [Google Scholar]
  18. Li C. H., Yamashiro D., Hammonds R. G., Jr, Westphal M. Synthetic insulin-like growth factor II. Biochem Biophys Res Commun. 1985 Mar 15;127(2):420–424. doi: 10.1016/s0006-291x(85)80177-7. [DOI] [PubMed] [Google Scholar]
  19. Little M. H., Ablett G., Smith P. J. Enhanced expression of insulin-like growth factor II is not a necessary event in Wilms' tumour progression. Carcinogenesis. 1987 Jun;8(6):865–868. doi: 10.1093/carcin/8.6.865. [DOI] [PubMed] [Google Scholar]
  20. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  21. Mizusawa H., Taira M., Yaginuma K., Kobayashi M., Yoshida E., Koike K. Inversely repeating integrated hepatitis B virus DNA and cellular flanking sequences in the human hepatoma-derived cell line huSP. Proc Natl Acad Sci U S A. 1985 Jan;82(1):208–212. doi: 10.1073/pnas.82.1.208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ogston C. W., Jonak G. J., Rogler C. E., Astrin S. M., Summers J. Cloning and structural analysis of integrated woodchuck hepatitis virus sequences from hepatocellular carcinomas of woodchucks. Cell. 1982 Jun;29(2):385–394. doi: 10.1016/0092-8674(82)90155-6. [DOI] [PubMed] [Google Scholar]
  23. Popper H., Roth L., Purcell R. H., Tennant B. C., Gerin J. L. Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc Natl Acad Sci U S A. 1987 Feb;84(3):866–870. doi: 10.1073/pnas.84.3.866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Popper H., Shih J. W., Gerin J. L., Wong D. C., Hoyer B. H., London W. T., Sly D. L., Purcell R. H. Woodchuck hepatitis and hepatocellular carcinoma: correlation of histologic with virologic observations. Hepatology. 1981 Mar-Apr;1(2):91–98. doi: 10.1002/hep.1840010202. [DOI] [PubMed] [Google Scholar]
  25. Rechler M. M., Nissley S. P. The nature and regulation of the receptors for insulin-like growth factors. Annu Rev Physiol. 1985;47:425–442. doi: 10.1146/annurev.ph.47.030185.002233. [DOI] [PubMed] [Google Scholar]
  26. Reeve A. E., Eccles M. R., Wilkins R. J., Bell G. I., Millow L. J. Expression of insulin-like growth factor-II transcripts in Wilms' tumour. Nature. 1985 Sep 19;317(6034):258–260. doi: 10.1038/317258a0. [DOI] [PubMed] [Google Scholar]
  27. Rogler C. E., Hino O., Su C. Y. Molecular aspects of persistent woodchuck hepatitis virus and hepatitis B virus infection and hepatocellular carcinoma. Hepatology. 1987 Jan-Feb;7(1 Suppl):74S–78S. doi: 10.1002/hep.1840070713. [DOI] [PubMed] [Google Scholar]
  28. Rogler C. E., Sherman M., Su C. Y., Shafritz D. A., Summers J., Shows T. B., Henderson A., Kew M. Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science. 1985 Oct 18;230(4723):319–322. doi: 10.1126/science.2996131. [DOI] [PubMed] [Google Scholar]
  29. Rogler C. E., Summers J. Cloning and structural analysis of integrated woodchuck hepatitis virus sequences from a chronically infected liver. J Virol. 1984 Jun;50(3):832–837. doi: 10.1128/jvi.50.3.832-837.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roth L., King J. M., Hornbuckle W. E., Harvey H. J., Tennant B. C. Chronic hepatitis and hepatocellular carcinoma associated with persistent woodchuck hepatitis virus infection. Vet Pathol. 1985 Jul;22(4):338–343. doi: 10.1177/030098588502200407. [DOI] [PubMed] [Google Scholar]
  31. Scott J., Cowell J., Robertson M. E., Priestley L. M., Wadey R., Hopkins B., Pritchard J., Bell G. I., Rall L. B., Graham C. F. Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues. Nature. 1985 Sep 19;317(6034):260–262. doi: 10.1038/317260a0. [DOI] [PubMed] [Google Scholar]
  32. Sell S., Hunt J. M., Knoll B. J., Dunsford H. A. Cellular events during hepatocarcinogenesis in rats and the question of premalignancy. Adv Cancer Res. 1987;48:37–111. doi: 10.1016/s0065-230x(08)60690-9. [DOI] [PubMed] [Google Scholar]
  33. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Soares M. B., Ishii D. N., Efstratiadis A. Developmental and tissue-specific expression of a family of transcripts related to rat insulin-like growth factor II mRNA. Nucleic Acids Res. 1985 Feb 25;13(4):1119–1134. doi: 10.1093/nar/13.4.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Soares M. B., Turken A., Ishii D., Mills L., Episkopou V., Cotter S., Zeitlin S., Efstratiadis A. Rat insulin-like growth factor II gene. A single gene with two promoters expressing a multitranscript family. J Mol Biol. 1986 Dec 20;192(4):737–752. doi: 10.1016/0022-2836(86)90025-2. [DOI] [PubMed] [Google Scholar]
  36. Summers J. Physical map of polyoma viral DNA fragments produced by cleavage with a restriction enzyme from Haemophilus aegyptius, endonuclease R-HaeIII. J Virol. 1975 Apr;15(4):946–953. doi: 10.1128/jvi.15.4.946-953.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Summers J., Smolec J. M., Snyder R. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4533–4537. doi: 10.1073/pnas.75.9.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Widmer U., Schmid C., Zapf J., Froesch E. R. Effects of insulin-like growth factors on chick embryo hepatocytes. Acta Endocrinol (Copenh) 1985 Feb;108(2):237–244. doi: 10.1530/acta.0.1080237. [DOI] [PubMed] [Google Scholar]
  39. Wong-Staal F., Gallo R. C. Human T-lymphotropic retroviruses. Nature. 1985 Oct 3;317(6036):395–403. doi: 10.1038/317395a0. [DOI] [PubMed] [Google Scholar]
  40. Yoshimura H., Harris R., Yokoyama S., Takahashi S., Sells M. A., Pan S. F., Lombardi B. Anaplastic carcinomas in nude mice and in original donor strain rats inoculated with cultured oval cells. Am J Pathol. 1983 Mar;110(3):322–332. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES