Tong Wei-Min, Cortes Ulrich, Hande M Prakash, Ohgaki Hiroko, Cavalli Luciane R, Lansdorp Peter M, Haddad Bassem R, Wang Zhao-Qi
International Agency for Research on Cancer (IARC), 69008 Lyon, France.
Cancer Res. 2002 Dec 1;62(23):6990-6.
Liver cancer is one of the major human tumors in the world. Basic and epidemiological studies have proposed that the major risk factors for liver cancer include alcohol and diet as well as infection with hepatitis B and C viruses. However, the mechanistic clues for the development of this type of cancer is largely unknown. Poly(ADP-ribose) polymerase (PARP-1) and a component of nonhomologous end-joining (NHEJ) machinery, Ku80, are two major DNA end-binding molecules that play a multifunctional role in DNA damage signaling and repair, recombination as well as the maintenance of genomic stability. Here we show that the interaction of PARP-1 and Ku80 is essential for development because PARP-1/Ku80 double null mice died at embryonic day (E) 9.5. Interestingly, haplo-insufficiency of Ku80 in PARP-1-/- mice promotes the development of hepatocellular adenoma and hepatocellular carcinoma (HCC). These tumors exhibited a multistage tumor progression associated with the loss of E-cadherin expression and the mutation of beta-catenin. Cytogenetic analysis revealed that Ku80 heterozygosity elevated chromosomal instability in PARP-1-/- cells and that these liver tumors harbored a high degree of chromosomal aberrations including fragmentations, end-to-end fusions, and recurrent nonreciprocal translocations (NRT). These features are reminiscent of human HCC. Taken together, these data implicate a synergistic function of Ku80 and PARP-1 in minimized chromosome aberrations and cancer development and suggest that defects in DNA end-processing molecules may be etiological factors in human HCC formation.
肝癌是全球主要的人类肿瘤之一。基础研究和流行病学研究表明，肝癌的主要风险因素包括酒精、饮食以及乙型和丙型肝炎病毒感染。然而，这种类型癌症发生发展的机制线索在很大程度上尚不清楚。聚（ADP - 核糖）聚合酶（PARP - 1）和非同源末端连接（NHEJ）机制的一个组成部分Ku80是两种主要的DNA末端结合分子，它们在DNA损伤信号传导与修复、重组以及基因组稳定性维持中发挥多功能作用。在此我们表明，PARP - 1与Ku80的相互作用对发育至关重要，因为PARP - 1/Ku80双敲除小鼠在胚胎期第9.5天死亡。有趣的是，在PARP - 1基因敲除小鼠中Ku80单倍体不足促进了肝细胞腺瘤和肝细胞癌（HCC）的发生发展。这些肿瘤呈现出与E - 钙黏蛋白表达缺失和β - 连环蛋白突变相关的多阶段肿瘤进展。细胞遗传学分析显示，Ku80杂合性增加了PARP - 1基因敲除细胞中的染色体不稳定性，并且这些肝肿瘤具有高度的染色体畸变，包括片段化、端对端融合和反复出现的非相互易位（NRT）。这些特征使人联想到人类肝癌。综上所述，这些数据表明Ku80和PARP - 1在最小化染色体畸变和癌症发生发展中具有协同功能，并提示DNA末端加工分子的缺陷可能是人类肝癌形成的病因学因素。
