(Applicants' Abstract): This research project makes use of autoantibodies in patients with hepatocellular carcinoma (HCC) and other types of cancer to isolate target antigens. The rationale is that intracellular proteins, which are involved in carcinogenesis, are provoking autoantibody responses and therefore autoantibodies can be used to immunoscreen cDNA expression libraries to isolate, identify and characterize proteins which might be involved in malignant transformation. This application is focused on two novel antigens: p62 and SG2Na. P62 binds to Insulin-like growth factor-II messenger RNA (IGF-II mRNA) leader 3 mRNA which is developmentally regulated, expressed in fetal tissues but not in adult tissues. Preliminary studies show that p62 is ectopically expressed in cancer nodules in at least 25 percent of HCC tissue specimens and it is postulated that autoantibodies represent immune system recognition of this aberrant expression. Dr. Tan proposes to produce transgenic mice with the anticipation that p62 ectopic expression will lead to upregulation of IGF-II expression and tumor formation, since high expression of IGF-II has been linked with carcinogenesis in many studies. We will also investigate other potential targets of p62 and a likely candidate is a protein p90 that appears to be an autoantigen frequently linked with p62 ectopic expression. A second project is analysis of another novel autoantigen in cancer called SG2NA, a nuclear protein that is highly expressed in S and G2 phases of the cell cycle. A domain in the N-terminus of SG2NA has transcription activating property and studies are proposed to determine whether this activation domain is involved in transformation using chicken embryo fibroblast assay. Other studies are to determine the target genes(s) of SG2NA and potential protein binding partners. Elucidation of the properties and function of these proteins might contribute to understanding co-activating factors in carcinogenesis.
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