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表观遗传与遗传调控在实体瘤中 KEAP1/NRF2 轴的失衡：聚焦甲基化和非编码 RNA。

Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs.

机构信息

Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy.

出版信息

Oxid Med Cell Longev. 2018 Mar 13;2018:2492063. doi: 10.1155/2018/2492063. eCollection 2018.

DOI:10.1155/2018/2492063
PMID:29643973
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5872633/
Abstract

Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch-like erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo- and radiotherapy resistance of cancer cells. In solid tumors, the KEAP1/NRF2 system is constitutively activated by the loss of or gain of functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes. In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation. This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.

摘要

细胞中的氧化和亲电变化主要由 KEAP1/NRF2（Kelch 样红细胞衍生的 cap-n-collar 同源物（ECH）相关蛋白 1/核因子（红细胞衍生 2）样 2）轴协调。这两种蛋白质之间的物理相互作用促进了几种抗氧化防御基因的表达，以响应外源性和内源性刺激。最近的研究表明，KEAP1/NRF2 轴功能障碍也与肿瘤的进展以及癌细胞的化疗和放疗耐药密切相关。在实体瘤中，KEAP1/NRF2 系统通过缺失或获得功能而持续激活，导致其核积累，并增强许多细胞保护基因的转录。除了点突变外，还报道了表观遗传异常，如异常启动子甲基化以及 miRNA（miRNA）和长非编码 RNA（lncRNA）的失调，是 KEAP1/NRF2 轴调节的新兴机制。这篇综述将总结关于表观遗传机制调节实体瘤中 KEAP1/NRF2 级联的最新知识及其作为预后和预测分子标志物的潜在用途。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/58fe1904efb5/OMCL2018-2492063.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/11251c825f28/OMCL2018-2492063.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/2026e0d4fda9/OMCL2018-2492063.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/58fe1904efb5/OMCL2018-2492063.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/11251c825f28/OMCL2018-2492063.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/2026e0d4fda9/OMCL2018-2492063.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6796/5872633/58fe1904efb5/OMCL2018-2492063.003.jpg

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