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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Cancer 1/2018

Gene-expression signature regulated by the KEAP1-NRF2-CUL3 axis is associated with a poor prognosis in head and neck squamous cell cancer

BMC Cancer > Ausgabe 1/2018
Akhileshwar Namani, Md. Matiur Rahaman, Ming Chen, Xiuwen Tang
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-017-3907-z) contains supplementary material, which is available to authorized users.



NRF2 is the key regulator of oxidative stress in normal cells and aberrant expression of the NRF2 pathway due to genetic alterations in the KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2 like 2)-CUL3 (cullin 3) axis leads to tumorigenesis and drug resistance in many cancers including head and neck squamous cell cancer (HNSCC). The main goal of this study was to identify specific genes regulated by the KEAP1-NRF2-CUL3 axis in HNSCC patients, to assess the prognostic value of this gene signature in different cohorts, and to reveal potential biomarkers.


RNA-Seq V2 level 3 data from 279 tumor samples along with 37 adjacent normal samples from patients enrolled in the The Cancer Genome Atlas (TCGA)-HNSCC study were used to identify upregulated genes using two methods (altered KEAP1-NRF2-CUL3 versus normal, and altered KEAP1-NRF2-CUL3 versus wild-type). We then used a new approach to identify the combined gene signature by integrating both datasets and subsequently tested this signature in 4 independent HNSCC datasets to assess its prognostic value. In addition, functional annotation using the DAVID v6.8 database and protein-protein interaction (PPI) analysis using the STRING v10 database were performed on the signature.


A signature composed of a subset of 17 genes regulated by the KEAP1-NRF2-CUL3 axis was identified by overlapping both the upregulated genes of altered versus normal (251 genes) and altered versus wild-type (25 genes) datasets. We showed that increased expression was significantly associated with poor survival in 4 independent HNSCC datasets, including the TCGA-HNSCC dataset. Furthermore, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PPI analysis revealed that most of the genes in this signature are associated with drug metabolism and glutathione metabolic pathways.


Altogether, our study emphasizes the discovery of a gene signature regulated by the KEAP1-NRF2-CUL3 axis which is strongly associated with tumorigenesis and drug resistance in HNSCC. This 17-gene signature provides potential biomarkers and therapeutic targets for HNSCC cases in which the NRF2 pathway is activated.
Additional file 1: Table S1. List of differentially expressed genes obtained from the RNA-Seq analysis of altered versus normal samples. (XLS 48 kb)
Additional file 2: Table S2. List of differentially expressed genes obtained from the RNA-Seq analysis of altered versus wild-type samples. (XLS 29 kb)
Additional file 3: Table S3. List of differentially expressed genes obtained from the RNA-Seq analysis of wild-type versus normal samples. (XLS 49 kb)
Additional file 4: Table S4. List of NRF2-AREs identified in the -5 kb promoter regions of RAB6B, UCHL1 and TRIM16L genes. (XLS 38 kb)
Additional file 5: Table S5. Multivariate analysis of 17-gene signature in 4 independent cohorts (XLS 25 kb)
Additional file 6: Figure S1. Kaplan-Meier plots showing the survival analysis of TCGA-HNSCC cohort clinical variables: tumor grades G2 (A) and G3 (B); pathologic T stagesT1 (C) and T2 (D); and pathologic disease stages II (E) and III (F). (TIFF 798 kb)
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