The concept of antigen-driven autoimmune responses is the basis of this study to use antinuclear antibodies (ANAs) in hepatocellular carcinoma (HCC) as a model to identify other nuclear proteins which could be participating in carcinogenesis. Unique features about HCC are the high frequency (31%) of ANAs and dynamic changes in antibody responses during transformation from precursor chronic liver disease states to malignancy. A cDNA encoding alternative splicing factor HCC1 of the serine-arginine (SR) family has been isolated with this approach, and its relationship with carcinogenesis will be examined in HCC1 transgenic mice. Another cDNA encoding a cell cycle-related nuclear protein maximally expressed in S and G2, called SG2NA (SG2 nuclear antigen) will be analyzed for its role in cell cycle progression with complementation studies involving a yeast mutant. This ts mutant is deficient in CDC4, a yeast cell cycle protein which has similar structural motifs as SG2NA and is required for DNA replication and separation of the centrosome to form the poles of the mitotic spindle. Studies will be continued to identify other proteins involved in tumorigenesis with special emphasis devoted to using antibodies which are present during the precursor disease states (chronic hepatitis and liver cirrhosis CH/LC) and those which appear de novo with malignancy. HCC offers a unique opportunity for separating nuclear proteins involved in inflammatory conditions such as CH/LC from those involved in subsequent malignancy. Collaboration has been initiated and will be continued with hepatologists in Japan who have a cohort of about 600 patients with CH/LC under long-term clinical surveillance. Patients converting to HCC can be immediately identified and serum and liver biopsies obtained for these studies.
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