EXPERIMENTAL HEPATOCARCINOGENESIS

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Antisera to dehistonized chromatins of transplantable Novikoff hepatoma or primary hepatomas produced in rats by feeding hepatocarcinogens recognize a variety of antigens associated with the tumor chromatin and not detectable in normal, regenerating or fetal rat liver. Three of these antigens (p39, p49 and p56) were identified as cytokeratins. These antigens will be characterized and their relationships to nuclear DNA and nuclear structural proteins (lamins, matricins, chromosomal scaffolds) determined by DNA protein and protein:protein crosslinking. Monoclonal antibodies to these antigens, developed recently in our laboratory, will be used to detect the presence of these antigens in the crosslinks. DNA complementary to mRNA of the p39 antigen which is specific for rat carcinomas will be cloned and the resulting DNA probes will be used to study the transcriptional regulation of th is gene in livers of rats subjected to experimental hepatocarcinogenesis. Another, very heterogeneous, group of nuclear antigens becomes expressed during chemical hepatocarcinogenesis. These antigens are associated with nuclear matrix preparations. Monoclonal antibodies to several of these antigens will be used to determine whether this complex population of antigens is the result of transcriptional expression of new proteins or whether the antisera recognize a new kind of post-translational modification of proteins present in normal rat liver. The associations of these proteins with DNA in the nuclear matrix will be investigated along with studies on the expression of these antigens in transplantation tumors and in metastases of the primary hepatocarcinomas. Our principal aims are the elucidation of biological roles which the specific hepatoma associated cytokeratins and nuclear matrix antigens play in the initiation, promotion and maintenance of the malignant phenotype. In a more practical aspect, we will utilize the early appearance of these tumor-associated antigens to develop an in vitro assay for the detection of compounds with carcinogenic potential.