Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice
Defective DNA strand break repair causes chromosomal instability and accelerates liver carcinogenesis in mice
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DOI：
10.1002/hep.22194
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发表时间：
2008-06-01
期刊：
影响因子：
13.5
通讯作者：
Fausto, Nelson
中科院分区：
文献类型：
--
作者：
Teoh, Narci C.;Dan, Yock Young;Fausto, Nelson
染色体不稳定是肝细胞癌（HCC）的一个特征，但其起源和在肝癌发生中的作用尚不清楚。我们测试了非同源末端连接 (NHEJ) DNA 修复基因 Ku70 的缺陷是否与染色体异常和增强肝癌发生有关。雄性 Ku70 NHEJ 缺陷 (Ku70-/-)、杂合子 (Ku70 +/-) 和野生型 (WT) 小鼠在 15 天时注射二乙基亚硝胺 (DEN)（一种肝癌物质）。在第 3、6 和 9 个月时处死动物以评估肿瘤发生和肝细胞增殖。为了进行核型分析，从所有基因型的 Ku70 小鼠中产生的 HCC 中制备原代肝肿瘤细胞培养物。与 WT 同窝小鼠相比，注射 DEN 的 Ku70-/- 小鼠表现出加速的 HCC 发展。 Ku70-/- HCC 的 4、5、7、8、10、14 和 19 号染色体的数量和结构畸变出现克隆性增加，其中许多都概括了在人类 HCC 中观察到的等效染色体异常谱。 Ku70-/- HCC 显示出高增殖活性，细胞周期蛋白 D1 和增殖细胞核抗原表达增加、Aurora A 激酶活性、共济失调毛细血管扩张突变激酶和泛素化增强，以及通过蛋白酶体降解导致 p53 丢失，这些特征与人类 HCC 非常相似。结论：这些发现表明 NHEJ DNA 修复途径的缺陷可能参与细胞周期检查点的破坏，导致染色体不稳定并加速 HCC 的发展。
Chromosomal instability is a characteristic feature of hepatocellular carcinoma (HCC) but its origin and role in liver carcinogenesis are undefined. We tested whether a defect in the nonhomologous end-joining (NHEJ) DNA repair gene Ku70 was associated with chromosomal abnormalities and enhanced liver carcinogenesis. Male Ku70 NHEJ-deficient (Ku70-/-), heterozygote (Ku70 +/-), and wild-type (WT) mice were injected with diethylnitrosamine (DEN), a liver carcinogen, at age 15 days. Animals were killed at 3, 6, and 9 months for assessment of tumorigenesis and hepatocellular proliferation. For karyotype analysis, primary liver tumor cell cultures were prepared from HCCs arising in Ku70 mice of all genotypes. Compared to WT littermates, Ku70-/- mice injected with DEN displayed accelerated HCC development. Ku70-/- HCCs harbored clonal increases in numerical and structural aberrations of chromosomes 4, 5, 7, 8, 10, 14, and 19, many of which recapitulated the spectrum of equivalent chromosomal abnormalities observed in human HCC. Ku70-/- HCCs showed high proliferative activity with increased cyclin D1 and proliferating cell nuclear antigen expression, Aurora A kinase activity, enhanced ataxia telangiectasia mutated kinase and ubiquitination, and loss of p53 via proteasomal degradation, features which closely resemble those of human HCC. Conclusion: These findings demonstrate that defects in the NHEJ DNA repair pathway may participate in the disruption of cell cycle checkpoints leading to chromosomal instability and accelerated development of HCC.