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Review
. 2016 Feb 27:9:14.
doi: 10.1186/s13045-016-0246-5.

Emerging roles of Nrf2 signal in non-small cell lung cancer

Yijun Tian  1 , Qian Liu  1 , Xuelian He  2 , Xun Yuan  1 , Yuan Chen  1 , Qian Chu  3 , Kongming Wu  4
Affiliations
Review

Emerging roles of Nrf2 signal in non-small cell lung cancer

Yijun Tian et al. J Hematol Oncol. .

Abstract

Non-small cell lung cancer (NSCLC) causes considerable mortality in the world. Owing to molecular biological progress, treatments in adenocarcinoma have evolved revolutionarily while those in squamous lung cancer remain unsatisfied. Recent studies revealed high-frequency alteration of Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-like factor 2 (Keap1/Nrf2) pathway within squamous lung cancer, attracting researchers to focus on this particular pathway. In NSCLC patients, deregulated Nrf2 signal is recognized as a common feature at both DNA and protein level. Emerging associations between Nrf2 and other pathways have been elucidated. MicroRNA was also implicated in the regulation of Nrf2. Agents activating or antagonizing Nrf2 showed an effect in preclinical researches, reflecting different effects of Nrf2 during tumor initiation and progression. Prognostic evaluation demonstrated a negative impact of Nrf2 signal on NSCLC patients' survival. Considering the importance of Nrf2 signal in NSCLC, further studies are required in the future.

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Figures

Fig. 1
Fig. 1
Corresponding amino residuals within Keap1 BTB domain on tertiary structure. Amino residues marked in different colors with arrows showed its serial number on peptide chain. Simulation of tertiary structure was constructed using PDB file of 4CXI produced by Cleasby et al. [110]. PyMOL Molecular Graphics System was used to present this domain
Fig. 2
Fig. 2
Schematic illustration of pathways associated with Nrf2 signal. Keap1 assembles Cullin 3 and binds to the ETGE and DLG sites of Nrf2 through Kelch domain, leading to the degradation of Nrf2. In the absence of Keap1, Nrf2 translocates from cytoplasm to nuclear to bind with ARE in the promoter region of target gene, leading to the transcriptional activation of genes related to inflammation, detoxication, and metabolic regulation. However, Nrf2 activity could be modified by acetylation and deacetylation through NF-kappa B or ER pathway. Nrf2 activity could also be inhibited by Bach1 through competitively binding with ARE. Mutant K-ras promotes Nrf2 transcriptional through TPA responsive element. Several microRNAs have been shown to inhibit Nrf2 or Keap1. BTB Broad complex, Tramtrack, and Bric à brac, ARE antioxidant responsive element, ER estrogen receptor, Ub ubiquitin, CBP CREB-binding protein
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