EXPERIMENTAL HEPATOCARCINOGENESIS

抗移植性Novikoff肝癌或 通过喂食肝癌物质产生的大鼠原发性肝癌识别一种 多种抗原与肿瘤染色质相关，且不可检测 在正常、再生或胎鼠肝脏中。 这些抗原中的三种（p39， p49和p56）被鉴定为细胞角蛋白。 这些抗原将是 及其与核DNA和核结构的关系 通过DNA确定的蛋白质（核纤层蛋白、matricins、染色体支架） 蛋白质和蛋白质：蛋白质交联。 这些的单克隆抗体 抗原，最近在我们的实验室开发，将用于检测 这些抗原在交联中的存在。 DNA互补的mRNA 将克隆对大鼠癌特异的p39抗原， 所得DNA探针将用于研究转录调控 在实验性肝硬化大鼠的肝脏中， 肝癌发生 另一组非常异质的核抗原开始表达 在化学性肝癌发生过程中。 这些抗原与 核基质制备。 其中几种的单克隆抗体 抗原将被用来确定是否这个复杂的群体， 抗原是新蛋白质转录表达的结果， 抗血清是否识别一种新的翻译后 修饰存在于正常大鼠肝脏中的蛋白质。 的关联 这些蛋白质与DNA在核基质中将被研究沿着 通过研究这些抗原在移植肿瘤中的表达， 以及原发性肝癌的转移。 我们的主要目的是阐明生物学作用， 特异性肝癌相关细胞角蛋白和核基质抗原发挥作用 在恶性表型的启动、促进和维持中。 在一个更实际的方面，我们将利用这些早期出现的 肿瘤相关抗原，以开发用于检测 具有致癌潜力的化合物。

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.