International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B11. Functional Analysis of CRAD3 Overexpressed in Mouse Hepatocellular Carcinoma

Masaharu Sumii1, Takeshi Yamazaki2, Saburo Fukuda1, Norimichi Koike1, Jun Teishima1, Mamoru Takahashi1, Yuji Masuda1, Shiro Kominami2, Kenji Kamiya1
1Department of Developmental Biology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University,
Faculty of Integrated Arts and Sciences, Hiroshima University

We identified a mouse novel gene, cis-retinol/androgen short-chain dehydrogenase type 3 (CRAD3), which was overexpressed in mouse hepatocellular carcinomas (HCCs). CRAD3 had a high amino acid sequence homology with CRAD1 and CRAD2 (94.3% and 79.5% identity with CRAD1 and CRAD2, respectively). Because both CRAD1 and CRAD2 have oxidative 3a-hydroxysteroid dehydrogenase activities (oxidative 3a-HSD activities) and retinol dehydrogenase activities (RoDH activities) in the presence of NAD+ as a cofactor, we investigated these enzyme activities of CRAD3. The Km values of CRAD3 for 3a-adiol and androsterone were 0.04 ÁM and 0.1 ÁM, respectively. Compared with the reported Km values, CRAD3 has more powerful oxidative oxidative 3a-HSD activity than CRAD1 or CRAD2. In contrast, CRAD3 had little RoDH activities unlike CRAD1 and CRAD2.

The incidence of HCC in human is higher in men than in women. In diethylnitrosamine induced hepatocarcinogenesis, the area of preneoplastic liver lesions were significantly decreased by orchiectomy in male rats, and significantly increased by ovariectomy and the administration of testosterone in female rats. Thus, androgens promote hepatocarcinogenesis in human and rodents. In androgens, dihydrotestosterone is the most active form, which has the highest affinity to androgen receptors, and metabolized into inactive androgen, 3a-adiol. Current our study indicates that CRAD3 could oxidize 3a-adiol back to active androgen, dihydrotestosterone. Therefore, our data suggest that overexpressed CRAD3 may promote mouse hepatocarcinogenesis by increasing the yield of dihydrotestosterone from 3a-adiol.

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