Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival.

Joe G. N. Garcia,Zhongqing Qian,Christopher I. Gurguis,Ting Wang,Fang Fang,Jingzhu Lv,Anne E. Cress,Xiaoyan Xu,Qing Wen,Donna D. Zhang,Jeffrey R. Jacobson,Viswanathan Natarajan,Tong Zhou,Louise Hecker

doi:10.1038/srep16889

Abstract

Nuclear factor, erythroid 2-like 2 (NFE2L2), a transcription factor also known as NF-E2-related factor 2 (Nrf2), is a key cytoprotective gene that regulates critical antioxidant and stress-responsive genes. Nrf2 has been demonstrated to be a promising therapeutic target and useful biomarker in malignant disease. We hypothesized that NFE2L2-mediated gene expression would reflect cancer severity and progression. We conducted a meta-analysis of microarray data for 240 NFE2L2-mediated genes that were enriched in tumor tissues. We then developed a risk scoring system based on NFE2L2 gene expression profiling and designated 50 tumor-associated genes as the NFE2L2-associated molecular signature (NAMS). We tested the relationship between this gene expression signature and both recurrence-free survival and overall survival in lung cancer patients. We find that NAMS predicts clinical outcome in the training cohort and in 12 out of 20 validation cohorts. Cox proportional hazard regressions indicate that NAMS is a robust prognostic gene signature, independent of other clinical and pathological factors including patient age, gender, smoking, gene alteration, MYC level, and cancer stage. NAMS is an excellent predictor of recurrence-free survival and overall survival in human lung cancer. This gene signature represents a promising prognostic biomarker in human lung cancer.

Highlights

Nuclear factor, erythroid 2-like 2 (NFE2L2), known as NF-E2-Related Factor 2 (Nrf2), is a transcription factor encoded by the NFE2L2 gene in humans[1]
At the specified significance level of false discovery rate (FDR) < 0.01 and fold change > 2, 1631 probe sets encoding 1172 genes were found to be up-regulated in NFE2L2 KD cells, while 792 probe sets for 593 genes were down-regulated in NFE2L2 KD cells (Supplementary Table S1)
We found that the number of Kyoto Encyclopedia of Genes and Genomes (KEGG) cancer pathways of the NFE2L2-mediated genes is significantly larger than that of the random gene sets (P = 0.002) (Supplementary Fig. S1)

Summary

Introduction

Erythroid 2-like 2 (NFE2L2), known as NF-E2-Related Factor 2 (Nrf2), is a transcription factor encoded by the NFE2L2 gene in humans[1]. As a central regulator of antioxidant genes, NFE2L2 has received great attention for its pivotal role in a number of pathologic conditions, including cancer[7–10]. Nrf[2] activators have been used in clinical trials for cancer therapy and the treatment of diseases associated with oxidative stress; on the other hand, constitutive activation of Nrf[2] in many types of tumors contributes to the survival and growth of cancer cells, as well as resistance to anticancer therapy[20]. Manipulation of Nrf[2] has become of great interest with regard to its use in therapy and the diagnosis/prognosis of malignant diseases. In this present study, we conducted secondary analysis of genome-wide expression data to identify NFE2L2-associated genes implicated in cancer pathobiology. We found that an NFE2L2-mediated gene signature could effectively predict lung cancer survival

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