De Miglio, Maria Rosaria and Simile, Maria Maddalena and Muroni, Maria Rosaria and Pusceddu, Stefano and Calvisi, Diego Francesco and Carru, Angelo and Seddaiu, Maria Antonietta and Daino, Lucia and Deiana, Luca and Pascale, Rosa Maria and Feo, Francesco (1999) Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible Wistar rat strain. Molecular Carcinogenesis, Vol. 25 (1), p. 21-29. ISSN 0899-1987. Article.
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Persistent liver nodules (Pns) and hepatocellular carcinomas (HCCs) induced in F344 rats by the resistant hepatocyte (RH) model exhibit c-myc overexpression and amplification. The role of these changes in progression of PN was investigated in nodules with different propensities to evolve to HCC in resistant Wistar rats and, for comparison, in susceptible F344 rats. Initiation of rats with diethylnitrosamine was followed by selection with 2-acetylaminofluorene (AAF) plus partial hepatectomy (RH groups). Two additional Wistar rat groups received a second AAF treatment without (RH+AAF) and with a necrogenic dose of Ccl4 (RH+AAF/CCl4) 15 d after selection. The number to liver ratio and volume of glutathione-S-transferase placental form-positive lesions were lower in the Wistar than the F344 RH groups 9 and 32 wk after initiation and increased after a second AAF cycle treatment with and without Ccl4. DNA synthesis in glutathione-S-transferase placental form-positive lesions was low in Wistar RH group at 9 wk and was stimulated by additional AAF treatments. HCCs developed at 57-60 wk in F344 RH, Wistar RH+AAF, and RH+AAF/CCl4 rats. Tumor incidence and multiplicity were lower in RH+AAF rats than in RH+AAF/CCl4 and F344 rats. At 32 wk, PN exhibited c-myc overexpression that increased from RH to RH+AAF rats and to RH+AAF/CCl4 Wistar rats. This was associated with c-myc amplification in Wistar RH+AAF/CCl4 rats. These results showed correlation of c-myc overexpression and amplification with nodule propensity to progress to HCC in poorly susceptible Wistar rats and suggested a possible genetic mechanism for susceptibility to hepatocarcinogenesis. The experimental system used in this work may be a valuable tool for studies on molecular mechanisms underlying liver growth and tumorigenesis supported by c-myc overexpression.
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