Abstract
Previous reports indicate that the expression of transforming growth factor α (TGF-α) is increased in enzyme-altered foci (EAF) arising in livers of rats treated with a carcinogen. Here we have investigated the effects of TGF-α on EAF cells in vitro. Hepatocytes were isolated from rats that had received repeated treatment with diethylnitrosamine (DEN) and whose livers contained glutathione S-transferase P (GST-P)-positive EAF. Primary cultures of GST-P-positive and GST-P-negative hepatocytes were exposed to TGF-α. TGF-α (20–40 ng/ml) increased DNA replication in the GST-P-negative, but not in the GST-P-positive cells. Furthermore, it was shown that this effect on GST-P-negative cells could be blocked by p53 antisense oligonucleotides. We conclude that EAF hepatocytes do not respond to TGF-α in vitro. This lack of response may reflect the attenuated expression of p53 in these cells. These data corroborate previous findings that, in response to DNA damage, many EAF hepatocytes do not accumulate p53.
Similar content being viewed by others
References
Bellamy COC, Clark AR, Wyllie AH, Harrison DJ. p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. FASEB J. 1997;11:591-9.
Burr AW, Toole K, Matthew J, Hines JE, Chapman C, Burt AD. Transforming growth factor-α expression is altered during experimental hepatocarcinogenesis. J Hepatol. 1996;179:276-82.
DeCicco LA, Kong J, Ringer DP. Carcinogen-induced alteration in liver epidermal growth factor receptor distribution during the promotion stage of hepatocarcinogenesis in rats. Cancer Lett. 1997;111:149-56.
Greenhalgh DA, Wang X-J, Donehower LA, Roop DR. Paradoxical tumor inhibitory effect of p53 loss in transgenic mice expressing epidermal-targeted v-rasHa, v-fos, or human transforming growth factor α. Cancer Res. 1996;56:4413-23.
Kaufmann WK, Zhang Y, Kaufmann DG. Association between expression of TGFα and progression of hepatocellular foci to neoplasms. Carcinogenesis. 1992;13:1481-3.
Lee GH, Merlino G, Fausto N. Development of liver tumors in transforming growth factor-α transgenic mice. Cancer Res. 1992;52:5162-70.
Lennartsson P, Högberg J, Stenius U. Wild-type p53 expression in liver tissue and in enzyme-altered foci; an in vivo investigation on diethylnitrosamine-treated rats. Carcinogenesis. 1998;19:1231-7.
Manjeshwar S, Rao PM, Rajalakshmi S, Sarma DSR. Inhibition of DNA synthesis by phenobarbital in primary cultures of hepatocytes from normal rat liver and from hepatic nodules. Carcinogenesis. 1992;13:2287-91.
Ogasawara H, Hiramoto J, Shirahama K et al. Hepatocyte growth factor stimulates the growth of hepatocytes in altered foci and hyperplastic nodules induced by chemical hepatocarcinogenesis in rats. Int Hepat Commun. 1995;3:296-304.
Pitot HC. Altered hepatic foci: their role in murine hepato-carcinogenesis. Annu Rev Pharmacol Toxicol. 1990;30:465-500.
Reddy KB, Chen YO. Molecular mechanism of EGF induced apoptosis in cancer cells. Abstract, AACR annual meeting, New Orleans, 1998:142.
Schulte-Hermann R, Bursch W, Grasl-Kraupp B, Mullauer L, Ruttkay-Nedecky B. Apoptosis and multistage carcinogenesis in rat liver. Mutat Res Fundam Mol Mech Mutat. 1995;333:81-7.
Sheikh MS, Carrier F, Johnson AC, Ogdon SE, Fornace AJ Jr. Identification of an additional p53-responsive site in the human epidermal growth factor receptor gene promoter. Oncogene. 1997;15:1095-101.
Shi YE, Yager JD. Regulation of rat hepatocyte epidermal growth factor receptor by the liver tumor promoter ethinyl estradiol. Carcinogenesis. 1990;11:1103-9.
Stenius U. Different inhibition of DNA synthesis by transforming growth factor β and phenobarbital on GST-P-positive and GST-P-negative hepatocytes. Carcinogenesis. 1993;14:159-61.
Stenius U, Högberg J. GST-P positive hepatocytes isolated from rats bearing enzyme-altered foci show no signs of p53 induction and replicate even when their DNA contains strand breaks. Carcinogenesis. 1995;16:1683-6.
Stenius U, Warholm M, Martens U, Högberg J. Isolation of glutathione S-transferase P-positive hepatocytes from carcinogen treated rats by use of ethacrynic acid as selecting agent. Carcinogenesis. 1994;15:1561-6.
Tanno S, Ogawa K. Abundant TGFa precursor and EGF receptor expression as a possible mechanism for the preferential growth of carcinogen-induced preneoplastic and neoplastic hepatocytes in rats. Carcinogenesis. 1994;15:1689-94.
Tsuji K, Ogawa K. Recovery from ultraviolet-induced growth arrest of primary rat hepatocytes by p53 antisense oligonucleotide treatment. Mol Carcinogen. 1994;9:167-74.
Van Gijssel HE, Maassen CBM, Mulder GJ, Meerman JHN. p53 protein expression by hepatocarcinogens in the rat liver and its potential role in mitoinhibition of normal hepatocytes as a mechanism of hepatic tumour promotion. Carcinogenesis. 1997;18:1027-33.
Van Winkel LS, Isaac JM, Plopper CG. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse. Am J Pathol. 1997;151:443-59.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lennartsson, P., Stenius, U. & Högberg, J. p53 expression and TGF-α-induced replication of hepatocytes isolated from rats exposed to the carcinogen diethylnitrosamine. Cell Biol Toxicol 15, 31–39 (1999). https://doi.org/10.1023/A:1007598522366
Issue Date:
DOI: https://doi.org/10.1023/A:1007598522366