Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels
Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels
复制标题
Nrf2不同表达水平下化学诱导的肺肿瘤的基因组图谱
DOI：
10.1093/carcin/bgac041
复制
发表时间：
2022
期刊：
影响因子：
4.7
通讯作者：
Shibata Tatsuhiro
中科院分区：
文献类型：
--
作者：
Satoh Hironori;Arai Yasuhito;Furukawa Eisaku;Moriguchi Takashi;Hama Natuko;Urushidate Tomoko;Totoki Yasushi;Kato Mamoru;Ohe Yuichiro;Yamamoto Masayuki;Shibata Tatsuhiro
转录因子 Nrf2 在抗氧化应激反应、保护 DNA 免受损伤和 DNA 修复机制中发挥着至关重要的作用。 Nrf2 活性可减少癌症的发生，但 Nrf2 如何在致癌刺激下影响全基因组改变仍有待探索。尽管最近使用下一代测序进行的全基因组分析揭示了各种人类癌症中核苷酸突变和拷贝数改变的情况，但小鼠癌症模型中的基因组变化尚未得到彻底检查。我们使用Nrf2缺陷小鼠和Keap1-kd小鼠（后者表达高水平的Nrf2）使用氨基甲酸乙酯（氨基甲酸乙酯）诱导的肺癌发生模型，阐明了Nrf2表达水平与全外显子突变模式之间的关系。外显子组分析表明，单核苷酸和三核苷酸突变模式和Kras突变特征显着不同，并且依赖于Nrf2的表达水平。相对于Nrf2-wt和Keap1-kd肿瘤，Nrf2缺陷型肿瘤表现出较少的拷贝数改变。观察到的基因组改变趋势可能阻止 Nrf2 缺陷肿瘤进展为恶性肿瘤。我们首次在 Nrf2 功能获得或丧失的小鼠模型中展示化学诱导的肺部肿瘤的全外显子组测序结果。我们的结果表明，不同的 Nrf2 表达水平会导致不同的基因突变模式，这些突变模式是每种肿瘤基因型中不同致癌机制的基础。
The transcription factor Nrf2 plays a crucial role in the anti-oxidative stress response, protection of DNA from injury and DNA repair mechanisms. Nrf2 activity reduces cancer initiation, but how Nrf2 affects whole-genome alterations upon carcinogenic stimulus remains unexplored. Although recent genome-wide analysis using next-generation sequencing revealed landscapes of nucleotide mutations and copy number alterations in various human cancers, genomic changes in murine cancer models have not been thoroughly examined. We elucidated the relationship between Nrf2 expression levels and whole exon mutation patterns using an ethyl-carbamate (urethane)-induced lung carcinogenesis model employingNrf2-deficient andKeap1-kd mice, the latter of which express high levels ofNrf2. Exome analysis demonstrated that single nucleotide and trinucleotide mutation patterns and theKrasmutational signature differed significantly and were dependent on the expression level ofNrf2. TheNrf2-deficient tumors exhibited fewer copy number alterations relative to theNrf2-wt andKeap1-kd tumors. The observed trend in genomic alterations likely prevented theNrf2-deficient tumors from progressing into malignancy. For the first time, we present whole-exome sequencing results for chemically-induced lung tumors in theNrf2gain or loss of function mouse models. Our results demonstrate that different Nrf2 expression levels lead to distinct gene mutation patterns that underly different oncogenic mechanisms in each tumor genotype.