Genetic analysis for cancer risk estimation of low-dose radiation exposure.

低剂量辐射暴露癌症风险评估的遗传分析。

• 批准号: 09480123
• 负责人: KAMIYA Kenji
• 金额: $ 6.53万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09480123/
• 关键词: Mouse hepatoma; SDF-II; Radiation; VL30; gene expression; RAD54; genetic instability; homologus recombination; 放射線誘発肝癌; 肝癌細胞株; U3; CAP; LOH; レトロトランスポゾン

Genetic changes of radiation-induced mouse hepatomas was studied by analyzing the expression of mRNA and loss of heterozygosity (LOH). We used primary hepatomas and it's cell lines established in-vitro, and got following three results. 1) We tried to identify genes differntially expressed in primary hepatomas compared to normal liver by using differetial display technique. we found five over-expressed genes such as ATPase inhibitor, ribosomal protein L35. plasminogen activator inhibitors apolipoprotein A-IV.and 3-hydroxy-3-metyylglutaryl coenzyme A (HMG-CoA)synthase, and three under-expressed genes such as UDP glucuronosyltransferase-2.4-hydroxyphenylpyruvate dioxygenase. and phospholipid scramblase in primary hepatomas. 2) In hepatoma cell lines, we found the frequent LOH around the locus of Lci on chromosome 4, where C57BL mouse allele was preferentiafly lost. 3) We identified over-expressed two genes in hepatoma cells grown in soft agar culture. one was retrotransposon VL3O, the oth … More er was newly isolated gene, designated SDF-III which had homology to SDF-II.VL3O was highly expressed in testis, ovary, and adrenal gland. Analysis of the expression of VL3O mRNA in liver revealed that the expression of VL3O mRNA had changed from the weak expression of VL3O subgroup 3 in normal livers to the strong expression of VL3O subgroup 1 in hepatomas during hepato-carcinogenesis. The structure of SDF- III protein indicated that this protein was chaperon protein which located in luminal of endplasmic reticulum, and might play a role for protein assembly.The involvement of mutations in homologus recombination genes, members of the RAD52 epistasis group, was studied in human cancer. We found missense mutations at functional regions of RAD54 and the absence of the wild-type RAD54 expression resulting from aberrant, splicing in primary cancers. Furthermore, we cloned human RALD54 homologue, designated RAD54B, and found homozygous mutations at highly conserved position of RAD54B in primary lymphoma and colon cancer. These findings suggest that some cancers arise through alterations of the homologus recombination gene function. Less

我们使用原代肝癌及其体外建立的细胞系，通过分析mRNA的表达和杂合性丢失（LOH）来研究辐射诱导的小鼠肝癌的遗传变化，并得到以下三个结果。通过差异显示技术，我们发现了原发性肝癌与正常肝脏中差异表达的基因，例如ATP酶抑制剂、核糖体蛋白L35。激活剂抑制剂载脂蛋白 A-IV. 和 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 合酶，以及原发性肝癌中 UDP 葡萄糖醛酸基转移酶-2.4-羟基苯丙酮酸双加氧酶和磷脂扰乱酶等三种表达不足的基因。肝癌细胞系，我们发现该位点周围频繁出现LOH 4 号染色体上的 Lci，其中 C57BL 小鼠等位基因优先丢失 3) 我们在软琼脂培养物中生长的肝癌细胞中发现了两个基因过度表达，一个是逆转录转座子 VL3O，另一个是新分离的基因，命名为 SDF-。 III与SDF-II具有同源性。VL3O在睾丸、卵巢和肾上腺中高表达。肝脏中VL3O mRNA的表达分析表明。肝癌发生过程中VL3O mRNA的表达由正常肝脏中VL3O亚组3的弱表达转变为肝癌中VL3O亚组1的强表达。SDF-III蛋白的结构表明该蛋白是定位的伴侣蛋白。在内质网管腔中，可能对蛋白质组装发挥作用。同源重组基因突变的参与，RAD52上位性成员我们在人类癌症中发现了 RAD54 功能区的错义突变以及由于原发性癌症中的异常剪接而导致的野生型 RAD54 表达的缺失。此外，我们克隆了人类 RALD54 同源物，命名为 RAD54B，并发现了纯合子。原发性淋巴瘤和结肠癌中 RAD54B 高度保守位置的突变表明，某些癌症是通过同源重组基因功能的改变而产生的。

项目成果

Patek, C.E., et al.: "A zinc finger truncation of murine WR1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome." Proc.Natl.Acad.Sci.USA.(in press).

Patek, C.E. 等人：“小鼠 WR1 的锌指截断会导致 Denys-Drash 综合征的特征性泌尿生殖系统异常。”

Miyagawa,K.,et al.: "Genetic instability and cancer." Int.J.Hematol.67. 3-14 (1998)

Miyakawa,K.,et al.：“遗传不稳定性和癌症。”

Miyagawa, K., et al.: "Genetic instability and cancer." Int.J.Hematol.67. 3-14 (1998)

Miyakawa, K. 等人：“遗传不稳定性与癌症。”

Hosoya, N., et al.: "Mutation analysis of the WT1 gene in myelodysplastic syndromes." Jpn.J.Cancer Res.89. 821-824 (1998)

Hosoya, N. 等人：“骨髓增生异常综合征中 WT1 基因的突变分析。”

Miyagawa, K., et al.: "Mutations of the WT1 gene in childhood non-lymphoid hematological malignancies." Genes Chromo.Cancer. (in press).

Miyakawa, K. 等人：“儿童非淋巴血液恶性肿瘤中 WT1 基因的突变。”