Simile, Maria Maddalena and Pagnan, Gabriella and Pastorino, Fabio and Brignole, Chiara and De Miglio, Maria Rosaria and Muroni, Maria Rosaria and Asara, Giuseppina and Frau, Maddalena and Seddaiu, Maria Antonietta and Calvisi, Diego Francesco and Feo, Francesco and Ponzoni, Mirco and Pascale, Rosa Maria (2005) Chemopreventive N-(4-hydroxyphenyl)retinamide (fenretinide) targets deregulated NF-kB and Mat1A genes in early stages of rat liver carcinogenesis. Carcinogenesis, Vol. 26 (2), p. 417-427. ISSN 1460-2180. Article.
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Cell cycle deregulation is an early event of hepatocarcinogenesis. We evaluated the role of changes in activity of nuclear factor kB (NF-kB) and some related pathways in this alteration, and the interference of N-(4-Hydroxyphenyl)Retinamide (HPR), a retinoid chemopreventive for various cancer types, with these molecular mechanisms and the evolution of preneoplastic liver to cancer. Male F344 rats, initiated according to "resistant hepatocyte" model of liver carcinogenesis, received weekly 840 nmol of liposomal HPR (SL-HPR)/100 g body weight or empty liposomes, between 5 and 25 weeks after initiation. Inhibition of DNA synthesis and induction of apoptosis occurred in precancerous lesions, 7-147 days after starting SL-HPR, and decrease in carcinoma incidence and multiplicity was observed, 25 weeks after arresting treatment. Increase in NF-kB expression and binding activity, and underexpression of inhibitor kB-α (IkB-α) were found in preneoplastic liver and neoplastic nodules, 5 and 25 weeks after initiation, respectively. These lesions also showed low expression of Mat1A and low activity of methionine adenosyltransferase I/III, whose reaction product, S-adenosyl-L-methionine, enhances IkB-α expression. SL-HPR prevented these changes and induced a decrease in expression of iNos, c-myc, cyclin D1 and Vegf-A genes, that were overexpressed in preneoplastic liver and nodules, and a decrease in Bcl-2/Bax, Bcl-2/Bad, and Bcl-xL/Bax mRNA ratios with respect to the lesions of control rats. Liposomes alone did not influence the parameters tested. These results indicate that signal transduction pathways controlled by NF-kB, nitric oxide, and S-adenosyl-L-methionine are deregulated in precancerous lesions. Recovery from these alterations by SL-HPR is associated with chemoprevention of hepatocarcinogenesis. Overall, these studies elucidate some molecular changes, in early stages of hepatocarcinogenesis, and underline their pathogenetic role. Moreover, they demonstrate a partially new mechanism of HPR chemopreventive effect and indicate the potential clinical relevance of this compound for prevention of hepatocellular carcinoma.
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