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NRF2 激活在癌症发生过程中的多方面后果。

The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis.

机构信息

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.

College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.

出版信息

Mol Cells. 2023 Mar 31;46(3):176-186. doi: 10.14348/molcells.2023.2191. Epub 2023 Mar 22.

Abstract

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.

摘要

细胞的氧化平衡由 Kelch 样 ECH 相关蛋白 1(KEAP1)/核因子红细胞 2 相关因子 2(NRF2)途径维持。这种细胞保护途径可解毒活性氧和外源性化学物质。KEAP1/NRF2 途径在致癌作用的各个阶段(包括启动、促进、进展和转移)中的作用是复杂的,作为致癌或抑癌作用。本篇综述重点介绍了描述 KEAP1/NRF2 途径如何在不同阶段影响癌症的关键研究。编译的数据表明,KEAP1/NRF2 在癌症中的作用高度依赖于背景;具体而言,使用的模型(化学诱导与遗传)、肿瘤类型和癌症阶段。此外,新出现的数据表明,KEAP1/NRF2 对于调节肿瘤微环境也很重要,其作用通过表观遗传学或对共存突变的反应来放大。为了开发改善患者预后的新型药理学工具和药物,需要进一步阐明该途径的复杂性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3155/10070161/d54a9eaf0abf/molce-46-3-176-f1.jpg

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