Carcinogenesis Advance Access published online on July 1, 2004
Carcinogenesis, doi:10.1093/carcin/bgh221
© 2004 by Oxford University Press
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1 Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy
* To whom correspondence should be addressed. E-mail: gmledda{at}unica.it.
Retinoids have been shown to exert an anticarcinogenic effect through suppression of cell cycle, induction of apoptosis and/or differentiation. In rat liver, in particular, retinoic acid has been shown to inhibit regeneration after partial hepatectomy, most probably through repression of the expression of c-fos and c-jun. Surprisingly enough, in spite of the proposed therapeutic effects of tRA, no data are available on its effect on normal adult liver. Here, we show that tRA administration in the diet (150 mg/kg) increased DNA synthesis in mouse liver, at 1 and 2 weeks, with a return to control values at 4 weeks (Labelling index was 16.5, 8.3 and 3.3%, respectively vs control values of 1.4, 1.3 and 2.5%). Increase in mitotic index paralleled that of BrdU incorporation. Kinetic studies showed that entry into S phase began between 24 and 48 hours, with a peak between 96 and 120 hours. Histological observation of the liver and biochemical evaluation of the levels of serum glutamate-pyruvate transaminases did not reveal any evidence of cell death demonstrating that increased DNA synthesis was not due to tRA-induced liver damage and regeneration, but rather the consequence of a direct mitogenic effect. In addition, analysis of total hepatic DNA content after a seven-day treatment showed a significant increase in tRA-fed mice compared to controls (21.11 mg/100 g body weight in tRA-fed mice vs 15.67 mg/100 g body weight of controls). Hepatocyte proliferation in tRA-fed mice was associated with increased hepatic levels of cyclin D1, E, and A, and enhanced expression of the member of pRb family, p107. In conclusion, the results showed that tRA induces hepatocyte proliferation in the absence of cell death, similarly to other ligands of steroid/thyroid hormone nuclear receptor superfamily. The mitogenic effect of tRA cautions about its possible use for antitumoral purposes in liver carcinogenesis.
Revised June 17, 2004
Accepted June 22, 2004
CANCER BIOLOGY
Induction of hepatocyte proliferation by retinoic acid
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