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Overexpression of Cysteine Sulfinic Acid Decarboxylase Stimulated by Hepatocarcinogenesis Results in Autoantibody Production in Rats¹

Department of Biology, Faculty of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263 [T. K., K. K., T. N., Y. M., T. W., Y. M., T. T.]; Biomedical Research and Development Department, Sumitomo Electric Industries, Limited., Taya-cho, Sakae-ku, Yokohama 254 [T. K., T. N.]; Department of Biological Science and Technology, Science University of Tokyo, Yamazaki, Noda 278 [E. H., K. O.]; and Department of Biochemistry, Faculty of Medicine, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-04 [M. M.], Japan

We developed a novel and efficient cDNA subtraction method to isolate rat hepatocellular carcinoma (HCC)-related genes. cDNAs from Solt-Farber procedure-driven HCCs were synthesized on Latex beads. The subtraction was accomplished by a simple centrifugation, PCR amplification, and dot blot screening. Among 2000 clones from the subtracted cDNA library, one clone with a full-length HCC-related cDNA was eventually obtained. Sequence analysis of this clone showed it to exhibit 90 and 60% similarity with the rat cysteine sulfinic acid decarboxylase (CSAD) and mammalian glutamic acid decarboxylases (GAD), respectively. Differences between our sequence data on CSAD and those reported previously were observed at two positions, which arose from a single amino acid substitution and frame shift mutation. The CSAD expression was restricted to the liver and kidney of rats. During hepatocarcinogenesis, expression of the CSAD mRNA and its protein was stimulated in the precancerous liver and maintained its high expression afterward. Interestingly, a high level of anti-CSAD autoantibody was detected in the HCC-bearing rats. The titer of anti-CSAD autoantibodies in these rats was 30–200 times higher than that in normal rats. The anti-CSAD autoantibody appeared in the precancerous state and was maintained afterward, and its pattern of appearance was similar to that of CSAD mRNAs and proteins. Thus, we propose that the high-titer CSAD autoantibody resulted from increased CSAD gene expression in the liver due to stimulation by the HCC. These results remind us of human autoimmune diseases including insulin-dependent diabetes mellitus and stiff-man syndrome, which are caused by autoantibodies against GAD.

¹ This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas and for Encouragement of Young Scientists from the Japanese Ministry of Education, Science, Sports and Culture, and by grants from the Asahi Glass Foundation, the Naito Foundation, and the Ciba-Geigy Foundation (Japan) for the Promotion of Science.

² To whom requests for reprints should be addressed. Phone: 81-43-290-2823; Fax: 81-43-290-2824.

Received 4/26/96. Accepted 9/16/96.

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