MacLeod A Kenneth, Acosta-Jimenez Lourdes, Coates Philip J, McMahon Michael, Carey Frank A, Honda Tadashi, Henderson Colin J, Wolf C Roland
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
Department of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Br J Cancer. 2016 Dec 6;115(12):1530-1539. doi: 10.1038/bjc.2016.363. Epub 2016 Nov 8.
Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question.
Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets.
AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours.
An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses.
尽管核因子红细胞2相关因子2（NRF2）通路是癌症中最常失调的通路之一，但尚不清楚突变状态是否是NRF2活性的良好预测指标。在此，我们利用醛酮还原酶（AKR）超家族的四个成员作为生物标志物来解决这个问题。
使用23种来源不同且NRF2通路突变状态各异的细胞系来确定AKR表达与NRF2活性之间的关系。在肺癌活检组织以及癌症基因组图谱（TCGA）和Oncomine数据集中评估AKR表达。
AKR在携带NRF2通路突变的细胞系中以较高的基础水平表达。在非突变细胞系中，NRF2激活后始终观察到AKR的协同诱导。对肺肿瘤活检组织的免疫组织化学分析以及对TCGA数据的研究表明，AKR在NRF2通路存在体细胞改变的鳞状细胞癌（SCC）和腺癌中均有富集，但就SCC而言，AKR在大多数其他肿瘤中也有富集。
AKR生物标志物 panel可用于确定肿瘤中的NRF2状态。NRF2通路的过度激活在肺SCC中比基因组分析先前预测的更为普遍。
