ALTERATIONS IN ENZYMATIC FUNCTIONS IN HEPATOCYTES AND HEPATOCELLULAR CARCINOMAS FROM RAS-TRANSDUCED LIVERS RESEMBLE THE EFFECTS OF INSULIN

An understanding of how oncogenes affect differentiated liver function s might lead to improved treatments for liver cancer or other disorder s where liver-specific functions are compromised. A retroviral vector that coexpressed beta-galactosidase (beta-gal) and activated Ras genes (Ras-gal) was transduced into a small fraction of adult rat hepatocyt es in vivo. Hepatocytes from Ras-gal-transduced diethylnitrosamine-unt reated livers and hepatocellular carcinomas (NCC) from Ras-gal-transdu ced diethylnitrosamine-treated rats were analyzed for liver functions by performing histochemical assays on liver sections. Ras-gal-transduc ed hepatocytes failed to express gluconeogenic, ketogenic, and urea pa thway enzymes. In contrast, several enzymes involved in fat synthesis were strongly activated, and microvesicular fat accumulated. These met abolic changes are induced in normal livers by insulin, a hormone that activates p21-ras. The deregulation of p21-ras may inhibit these live r-specific functions and may induce fat synthesis in both malignant an d nonmalignant liver diseases. Furthermore, treatment with drugs that inhibit the attachment of p21-ras to the plasma membrane might reverse these changes. The alterations in enzymatic functions in the HCCs wer e similar to those observed in the hepatocytes, although each of the t wo cancers had a region that abruptly lost its expression of liver-spe cific enzymes and acquired the expression of genes that are more chara cteristic of oval or bile ductule cells. This suggests that a single g enetic event in a malignant cell may dramatically alter its apparent p henotype. The identification of this putative gene might lead to insig hts into the regulation of the phenotype of normal cells in the liver.