活性氧化物 (ROS)，如自由基，对DNA具有诱变性，因此预测它们能促进肿瘤形成。然而这项研究表明，Kras、Braf 和 Myc 致癌基因在小鼠细胞中以内生水平表达，事实上会降低ROS水平。研究还发现，一些致癌基因能诱导转录因子Nrf2的表达，该因子的作用是使ROS失去毒性。与该发现相一致的是，Nrf2基因剔除后会抑制K-Ras-诱导胰腺肿瘤的形成。因此，调控细胞的氧化-还原状态是决定正常细胞转化成肿瘤的一个重要因素，所以它可能是一个潜在的治疗目标。
人体中细胞的氧化-还原状态与癌症的关系
生物探索推荐英文摘要
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
Abstract: Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer1. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2–5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2–Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic6. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-RasG12D, B-RafV619E and MycERT2 each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-RasG12D and B-RafV619E, and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-RasG12D-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.
