EGF- and CPA-induced mitogenic stimuli are differentially down-regulated by TGF-beta1 in cultured rat hepatocytes

Carcinogenesis
R Fasciati, P Maier

Abstract

Down-regulation of the mitogenic activity of the rodent liver carcinogen cyproterone acetate (CPA) and of epidermal growth factor (EGF) were compared in cultured rat hepatocytes. Both hepatomitogens produce an increase in the expression of proliferating cell nuclear antigen (PCNA) and in [3H]thymidine incorporation in a dose-dependent manner. In combination, the two mitogens induced an additive mitogenic response. Concomitant exposure to the growth inhibitory cytokine transforming growth factor beta1 (TGF-beta1) resulted in a differential dose-dependent down-regulation of PCNA-expressing cells. The corresponding down-regulation of CPA-induced PCNA expression required a 3- to 5-fold higher TGF-beta1 concentration than for EGF-induced expression. In contrast, CPA-exposed hepatocytes become vulnerable to and EGF-exposed cells protected against the apoptosis-inducing activity of TGF-beta1 (>0.1 ng/ml). Under culture conditions that mimicked a pericentral-equivalent microenvironment (low oxygen tension, low glucagon concentration), PCNA expression was 3-fold lower and CPA-specific resistance was no longer detectable. It is concluded that EGF and CPA induce their growth stimuli preferentially in the periportal area of the liver but i...Continue Reading

Citations

Jun 10, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·G SenaldiT Hartung
Aug 11, 2000·European Journal of Pharmacology·N Milosevic, P Maier
Oct 26, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Y ShimaN Ishii
Nov 3, 2010·Liver International : Official Journal of the International Association for the Study of the Liver·Eszter TurányiPeter Nagy
Sep 28, 2001·The Annals of Pharmacotherapy·N GiordanoC Gennari
Dec 15, 2006·World Journal of Gastroenterology : WJG·Ioanna SavidouSpyridon P Dourakis

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