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

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.

SUBMITTER: Tian Y

PROVIDER: S-EPMC4769825 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Tian Yijun Y Liu Qian Q He Xuelian X Yuan Xun X Chen Yuan Y Chu Qian Q Wu Kongming K

Journal of hematology & oncology 20160227

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, deregula ...[more]

PMID: 26922479

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Project description:BackgroundNuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs.Methods and findingsHere we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps.ConclusionsThis is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.

Dataset Information

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

Publications

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

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