Genetic analysis of radiation-induced mouse hepatomas

• Published in: International Congress series Vol. 1236; pp. 151 - 156
• Main Authors: Kamiya, Kenji, Sumii, Masaharu, Masuda, Yuji, Ikura, Tsuyoshi, Koike, Norimichi, Takahashi, Mamoru, Teishima, Jun
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.07.2002
• Subjects: CRAD; Hepatoma; Mutation; Radiation carcinogenesis; Rev1; Radiation carcinogenesis; SDRs; h6-mRev1; Rev1; HCC; Mutation; Hepatoma; 3α-HSD; CRAD; AP
• ISSN: 0531-5131; 1873-6157
• DOI: 10.1016/S0531-5131(02)00294-7

In order to understand the molecular mechanism of radiation carcinogenesis, we conducted two experiments. Firstly, we analyzed overexpressed 14 genes in radiation-induced mouse hepatomas, including novel two genes named CRAD3, which was a member of cis-retinol/androgen dehydrogenase (CRAD) family, and Sdf2l1, which was a member of Pmt/rt family. CRAD plays an important role in androgen metabolism, which converts inactive 3α-adiol into active dihydrotestosterone and consequently increases androgen activity. Actually, oxidative 3α-hydroxysteroid dehydrogenase activity in mouse hepatomas was found to be higher than that in normal liver at physiological 3α-adiol level. Dihydrotestosterone is well known to promote hepatocarcinogenesis. Therefore, the overexpression of CRAD3 must modify the radiation-induced mouse hepatocarcinogenesis by increasing local dihydrotestosterone level. Secondly, we compared the mutation spectum of β-catenin and found that there were no statistical differences in the frequency and sites of β-catenin mutation between radiation-induced and spontaneous hepatomas. Since the similarity of mutation spectra between radiation-induced and spontaneous cancers was well documented, we try to clarify the involvement of spontaneous mutations in radiation carcinogenesis. We characterized mouse Rev1 gene which was a member of the UmuC/DinB/XPV gene family, played important roles in spontaneous mutations. Biochemical analysis of the mouse Rev1 protein revealed that the mouse Rev1 protein possessed not only deoxycytidyl transferase activity as human REV1 protein, but also the ability to insert a dGMP or a dTMP residue opposite template guanine and an AP site. The expression of mouse Rev1 gene of primary embryonic fibroblasts in culture was induced by radiation exposure. These observations might be important for the study of molecular mechanism in radiation carcinogenesis.