Correlation of c-myc overexpression and amplification with progression of preneoplastic liver lesions to malignancy in the poorly susceptible Wistar rat strain

Persistent liver nodules (PNs) and hepatocellular carcinomas (HCCs) induced in F344 rats by the resistant hepatocyte (RH) model exhibit c-myc over exp ression and amplification. The role of these changes in progression of PN w as investigated in nodules with different propensities to evolve to HCC in resistant Wistar rats and, for comparison, in susceptible F344 rats. Initia tion of rats with diethylnitrosamine was followed by selection with 2-acety laminofluorene (AAF) plus partial hepatectomy (RH groups). Two additional W istar 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-positiv e lesions were lower in the Wistar than the F344 RH groups 9 and 32 wk afte r initiation and increased after a second AAF cycle treatment with and with out CCl4. DNA synthesis in glutathione-5-transferase placental form-positiv e lesions was low in Wistar RH group at 9 wk and was stimulated by addition al AAF treatments. HCCs developed at 57-60 wk in F344 RH, Wistar RH+AAF, an d RH+AAF/CCl4 rats. Tumor incidence and multiplicity were lower in RH+AAF r ats than in RH+AAF/CCl4 and F344 rats. At 32 wk, PN exhibited c-myc overexp ression that increased from RH to RH+AAF rats and to RH+AAF/CCl4 Wistar rat s. 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 rat s and suggested a possible genetic mechanism for susceptibility to hepatoca rcinogenesis. The experimental system used in this work may be a valuable t ool for studies on molecular mechanisms underlying liver growth and tumorig enesis supported by c-myc overexpression. (C) 1999 Wiley-Liss, Inc.