GLYCOSYLATION IN EXPERIMENTAL LIVER CARCINOGENESIS

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The long term objective of this study is to uncover the relevance of glycosylation of glycoproteins in carcinogenic process. The process proposal stems from recent discovery that the hepatic nodules of rats initiated with a hepatocarcinogen and promoted with orotic acid expressed a novel glycosyl transferase, N-acetyl glucosaminyltransfease III (GnT III) involved in the synthesis of bisecting N-acetylglucosamine residue in N-linked oligosaccharides of cellular glycoproteins. The significance of this observation lies in the fact that in liver tissue the bisecting structures are detected only in hepatocellular carcinoma and not in the normal liver cell glycoproteins. Experiments have been designed to ascertain at what stage during hepatocarcinogenesis the novel enzyme is induced and whether the induced enzyme persists throughout the process. For this purpose rats will be initiated with a liver carcinogen and promoted with orotic acid. Rats will be killed at various times afterwards and the liver nodules and cancers will be monitored for the presence of GnT III. The enzyme will also be purified from the nodules and antibody prepared. Using the antibody and immunohistochemical methods early microscopic putative preneoplastic lesions including initiated hepatocystes will be monitored for the presence of GnT III. The significance of this study is that cancer related glycosylation patterns and induction of new glycosyl transferases have been studied mostly in frank carcinomas and other malignant lesions and the present study is first of its kind to probe into these important aspects in systematic manner during the entire carcinogenic process. With the information generated from this study we will in a better position to assess the significance of glycosyl transferases in the carcinogenic process as well as in the diagnosis and prognosis of cancer in human.