Division of Pathology, National Institute of Health Sciences, Kawasaki, Japan.
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Cancer Sci. 2024 Nov;115(11):3612-3621. doi: 10.1111/cas.16324. Epub 2024 Sep 8.
Chromosome aberrations (CAs), a genotoxic potential of carcinogens, are believed to contribute to tumorigenesis by chromosomal rearrangements through micronucleus formation. However, there is no direct evidence that proves the involvement of CAs in tumorigenesis in vivo. In the current study, we sought to clarify the involvement of CAs in chemical carcinogenesis using a rat model with a pure CA-inducer hepatocarcinogen, acetamide. Whole-genome analysis indicated that hepatic tumors induced by acetamide treatment for 26-30 weeks showed a broad range of copy number alterations in various chromosomes. In contrast, hepatic tumors induced by a typical mutagen (diethylnitrosamine) followed by a nonmutagen (phenobarbital) did not show such mutational patterns. Additionally, structural alterations such as translocations were observed more frequently in the acetamide-induced tumors. Moreover, most of the acetamide-induced tumors expressed c-Myc and/or MDM2 protein due to the copy number gain of each oncogene. These results suggest the occurrence of chromosomal rearrangements and subsequent oncogene amplification in the acetamide-induced tumors. Taken together, the results indicate that CAs are directly involved in tumorigenesis through chromosomal rearrangements in an acetamide-induced hepatocarcinogenesis rat model.
染色体畸变（CAs）是致癌物的遗传毒性潜能，通过微核形成导致染色体重排，被认为有助于肿瘤发生。然而，目前尚无直接证据证明 CAs 参与体内肿瘤发生。在本研究中，我们使用纯 CA 诱导物肝致癌物乙酰胺的大鼠模型，试图阐明 CAs 在化学致癌中的作用。全基因组分析表明，乙酰胺处理 26-30 周诱导的肝肿瘤在各种染色体上显示出广泛的拷贝数改变。相比之下，由典型诱变剂（二乙基亚硝胺）继非诱变剂（苯巴比妥）诱导的肝肿瘤没有表现出这种突变模式。此外，在乙酰胺诱导的肿瘤中观察到更多的结构改变，如易位。此外，由于每个癌基因的拷贝数增加，大多数乙酰胺诱导的肿瘤表达 c-Myc 和/或 MDM2 蛋白。这些结果表明在乙酰胺诱导的肝癌发生大鼠模型中，染色体重排和随后的癌基因扩增的发生。总之，这些结果表明 CAs 通过乙酰胺诱导的肝癌发生大鼠模型中的染色体重排直接参与肿瘤发生。
