Analysis of molecular mechanism of radiation-induced cancer and risk estimation

辐射诱发癌症的分子机制分析及风险评估

• 批准号: 11680549
• 负责人: KAMIYA Kenji
• 金额: $ 2.37万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680549/
• 关键词: CRAD; REV1; Sdf211; hepatoma; error-prone DNA repair; mutation; androgen; endreticulum stress; 放射線; 遺伝子損傷; 遺伝子発現; translesion DNA合成; 放射線発がん; SDF2L1; 小胞体蛋白; ストレス蛋白; DNA修復; 損傷乗り越えDNA複製; マウス肝癌; 放射線誘発肝癌; 肝癌細胞株; CRAD1; CRAD2; CRAD3

To clarify the molecular mechanism of radiation-carcinogenesis, and apply it to the risk estimation, we conducted two experiments. Firstly, we analyzed the expression of genes in radiation-induced-mouse hepatomas. Mouse hepatomas were induced in B6C3F1 mice by 3Gy of ^<60>Coγ-ray exposure, and mRNAs were isolated from hepatomas and normal liver in the same mice. We identified differentially expressed genes by differential display technique. We found nineteen differentially expressed genes in hepatomas. Expressions of five genes were decreased and those of other fourteen genes were increase in hepatomas, including novel three genes named CRAD3 that was a member of cis-retinol/androgen dehydrogenase (CRAD) family, Sdf211 that was a member of Pmt/rt family, and A141-36 whose homology was not identified. CRAD plays an important role in androgen metabolism, which converts inactive 3α-adiol, into active dihydrotestosterone, (oxidative 3α-hydroxysteroid dehydrogenase activities : oxidative 3α … More -HSD activities) and consequently increases androgen activity. Actually, oxidative 3α-HSD 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 over-expression of CRAD3 must modify the radiation-induced mouse hepatocarcinogenesis by increasing local dihydrotestosterone level. Secondly, we try to clarify the involvement of spontaneous mutations in radiation carcinogenesis, because similarity of mutation spectra between radiation-induced and spontaneous cancers was well documented. We characterized mouse and human Revl 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 a deoxycytidyl transferase activity as human REV1 protein. The expression of mouse Rev1 gene of primary embryonic fibroblasts in culture was induced by radiation exposure. This observation might be important, because the biochemical property suggested that the activity of the Rev1 protein was required for bypassing oxidative DNA damage by translesioh DNA synthesis during DNA replication. Less

为了阐明放射致癌的分子机制，并将其应用于风险评估，我们进行了两个实验，首先，我们分析了3Gy^诱导的B6C3F1小鼠肝癌中的基因表达。 60 Coγ射线暴露，并从同一小鼠的肝癌和正常肝脏中分离mRNA。我们通过差异显示技术鉴定了差异表达的基因。我们发现了19个差异表达的基因。肝癌中 5 个基因表达降低，其他 14 个基因表达升高，其中包括顺式视黄醇/雄激素脱氢酶 (CRAD) 家族成员 CRAD3、Pmt/ 成员 Sdf211 等新发现的 3 个基因。 rt 家族和 A141-36 的同源性尚未确定，CRAD 在雄激素代谢中发挥重要作用，可转化无活性的 3α-二醇，转化为活性二氢睾酮（氧化 3α-羟基类固醇脱氢酶活性：氧化 3α ... 更多 -HSD 活性），从而增加雄激素活性。实际上，在生理 3α- 水平下，小鼠肝癌中的氧化 3α-HSD 活性高于正​​常肝脏。众所周知，二氢睾酮水平会促进肝癌发生，因此，CRAD3 的过度表达必须改变。其次，我们试图阐明自发突变在放射致癌过程中的作用，因为我们对小鼠和人类 Revl 基因的突变谱的相似性进行了详细记录。是 UmuC/DinB/XPV 基因家族的成员，在小鼠 Rev1 蛋白的自发突变中发挥重要作用，小鼠 Rev1 蛋白具有脱氧胞苷基转移酶活性。作为人类 REV1 蛋白，小鼠原代胚胎成纤维细胞 Rev1 基因的表达是由辐射暴露诱导的，这一观察结果可能很重要，因为生化特性表明 Rev1 蛋白的活性是绕过损伤引起的氧化性 DNA 损伤所必需的。 DNA复制过程中DNA合成较少。

项目成果

Masuda, Y., Sumii, M., Fukuda, S., Takahashi, M., Teishima, J., Koike, N., Kamiya, K.: "Cloning and characterization of human REV1 gene"Nagasaki Medi. J.. 75. 246-248 (2000)

Masuda, Y.、Sumii, M.、Fukuda, S.、Takahashi, M.、Teishima, J.、Koike, N.、Kamiya, K.：“人类 REV1 基因的克隆和表征”Nagasaki Medi。

増田雄司, その他: "ヒトREV1遺伝子のクローニングと機能解析"長崎医学会雑誌. 75原爆特集号. 246-248 (2000)

Yuji Masuda等：“人类REV1基因的克隆和功能分析”长崎医学会杂志75号原子弹特刊（2000年）。

Kamiya, K., Nitta, Y.: "Genetic Susceptibility to Mammary Carcinogenesis in Rats, Stochastic Effects of Radiation and Their Modification - Carcinogenesis and Effects on Embryos/Fetuses -"Radiological Science, Vol. 42 Suppl. pp.45-52, Jitugyoukouhousha. (1

Kamiya, K., Nitta, Y.：“大鼠乳腺癌的遗传易感性、辐射的随机效应及其修饰 - 致癌作用及其对胚胎/胎儿的影响 -”放射学科学，卷。

Fukuda,S., et al.: "Murine and Human SDF2L1 is an Endoplasmie Reticulum Stress-inducible Gene and Encodes a New Member of Pmt/rt Protein Family."Biochem.Biophys.Res.Commun.. 280. 407-414 (2001)

Fukuda,S., et al.：“小鼠和人类 SDF2L1 是一种内质网应激诱导基因，编码 Pmt/rt 蛋白家族的新成员。”Biochem.Biophys.Res.Commun.. 280. 407-414（

Teishima, J., Yasumoto, H., Sumii, M., Masuda, Y., Fukuda, S., Takatiashi, M., Koike, N., Usui, T., Kamiya, K.: "Decreased Expression of IGFBP-7 Gene in Mouse Hepatomas."Clinical endocrinology. 48 Supple.. 149-153 (2000)

Teishima, J.、Yasumoto, H.、Sumii, M.、Masuda, Y.、Fukuda, S.、Takatiashi, M.、Koike, N.、Usui, T.、Kamiya, K.：“IGFBP 表达降低