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

为了阐明辐射致癌的分子机制，并将其应用于风险评估，我们进行了两个实验。首先，我们分析了辐射诱导的小鼠肝癌中基因的表达。用3Gy的~（60）Coγ射线诱发B6 C3 F1小鼠肝癌<60>，并从同一小鼠肝癌和正常肝脏中分离mRNA。通过差异显示技术筛选差异表达基因。我们在肝癌中发现了19个差异表达基因。其中5个基因表达降低，14个基因表达升高，包括顺式视黄醇/雄激素脱氢酶（cis-retinol/androgen dehydrogenase，CRAD）家族成员CRAD 3、Pmt/rt家族成员Sdf 211和同源性未鉴定的A141-36。CRAD在雄激素代谢中起重要作用，其将失活的3α-己二醇转化为活性的二氢睾酮（氧化3α-羟基类固醇脱氢酶活性：氧化3 α-己二醇脱氢酶活性： ...更多信息 -HSD活性），并因此增加雄激素活性。实际上，在生理3α-己二醇水平下，小鼠肝癌中的氧化3α-HSD活性高于正常肝脏。众所周知，双氢睾酮可促进肝癌的发生。因此，CRAD 3的过表达可能通过增加局部双氢睾酮水平来改善辐射诱导的小鼠肝癌发生。其次，我们试图阐明辐射致癌中的自发突变的参与，因为辐射诱发的癌症和自发性癌症之间的突变谱的相似性是有据可查的。我们对小鼠和人的Revl基因进行了鉴定，Revl基因属于UmuC/DinB/XPV基因家族，在自发突变中起重要作用。小鼠Rev 1蛋白的生化分析显示，小鼠Rev 1蛋白具有与人REV 1蛋白相同的脱氧胞苷酰转移酶活性。辐射诱导原代培养的胚胎成纤维细胞表达小鼠Rev 1基因。这一观察结果可能是重要的，因为生物化学性质表明，Rev 1蛋白的活性是在DNA复制过程中通过translesioh DNA合成绕过氧化DNA损伤所必需的。少

项目成果

神谷研二: "放射線の人体影響"Medical Practice. 17(6). 1064-1070 (2000)

Kenji Kamiya：“辐射对人体的影响”医学实践 17(6) (2000)。

Kamiya, K., et al.: "Kinetics of Mammary Clonogenic Cells and Rat Mammary Cancer Induction by X-rays or Fission Neutrons"J. Radiat. Res.. 40 Suppl. 128-137 (1999)

Kamiya, K. 等人：“X 射线或裂变中子诱导乳腺克隆细胞和大鼠乳腺癌的动力学”J。

Kamiya, K.: "Effects of radiation on human body."Medical Practile. 17 (6). 1064-1070 (2000)

Kamiya, K.：“辐射对人体的影响。”医学实践。

Matsuda, M., Miyagawa, K., Takahashi, M., Fukuda, T., Kataoka, T., Asahara, T., Inui, H., Watatani, M., Yasutomi, M,, Kamada, N., Dohi, K., Kamiya, Y.: "Mutations in the RAD54 recombination gene in primary cancers."Oncogene. 18. 3427-3430 (1999)

松田，M.，宫川，​​K.，高桥，M.，福田，T.，片冈，T.，麻原，T.，干，H.，渡谷，M.，康富，M，，镰田，N.，

Kamiya, K.: "Chapter 13 Diseases induced by intoxication or environmeat 7) Diseases induced by radiation."Internal Medicine II, pp.2229-2233, Bunkodo. (1999)

Kamiya, K.：“第 13 章中毒或环境引起的疾病 7) 辐射引起的疾病。”《内科 II》，第 2229-2233 页，Bunkodo。