The objective of this project is to characterize the role of retroviral associated oncogenes in both the formation and/or maintenance of hepatocellular carcinoma. The experimental systems presently under study are (A) a human hepatoma cell line, HEP G2 and (B) an in vivo rat model for chemically induced hepatocellular carcinoma. The results obtained with the HEP G2 study include the tumorigenic characterization of this cell line which may be associated with elevated levels of c-myc transcripts coupled to the expression of an """"""""activated"""""""" N-ras gene. Gene expression in the progressive development of chemically induced hepatocellular carcinoma in the rat was also examined. Early preneoplastic changes were examined by isolating preneoplastic foci hepatocytes (which lack the cell-surface asialoglycoprotein receptor) in addition to later stage preneoplastic nodules and hepatocellular carcinomas. In this system, four genes are being analyzed in detail: ornithine decarboxylase (associated with proliferation); alphe-fetoprotein (associated with a less differentiated state); p53 (associated with the transformed phenotype); and myc (associated with certain human malignancies). Changes in expression of these four genes were characteristic of late stage changes rather than early premalignant changes. Finally, the modulation of the asialoglycoprotein receptor in the carcinogenic process was shown to be a post-transcriptional event in vivo.
