Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis.
As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer.
Mutations in KEAP1/NFE2L2 genes always cause persistent Nrf2 activation in lung cancer cells that confer therapeutic resistance and aggressive tumorigenic activity, dictating either poor prognosis or short duration of response to chemotherapy in clinical observations.
They found that lico A significantly promoted the tumor-suppressor miR-144-3p expression, so as to up-regulate ER stress-response protein CHOP (CCAAT/-enhancer-binding protein homologous protein) by down-regulating nuclear factor E2-related factor 2 (Nrf2), finally inducing apoptotic cell death in lung cancer.
Importantly, potential avenues and implications for therapeutic targeting of KEAP1-NRF2 pathway vulnerabilities for lung cancer patients will be highlighted.
Intriguingly, the signalling molecules perturbed by CCRK are divergent and cancer-specific, including the cell cycle regulators CDK2, cyclin D1, cyclin E and RB in glioblastoma, ovarian carcinoma and colorectal cancer, and KEAP1-NRF2 cytoprotective pathway in lung cancer.
Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease.
In excellent agreement with this finding, we found that minor A/A homozygotes of a single nucleotide polymorphism (SNP) in the human NRF2 upstream promoter region (rs6721961) exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked.
Nrf2 activation also stimulated growth of lung cancer-derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions.
Association of loss of function with promoter polymorphisms in NRF2 or somatic and epigenetic mutations in KEAP1 and NRF2 has been found in cohorts of patients with acute lung injury/acute respiratory distress syndrome or lung cancer, which further supports the role for NRF2 in these lung diseases.
This study investigated the expression of Nrf2 and of Nrf2-targeted genes (NQO1 and GCLC) and the genes for the metallothionein (MT) isoforms (MT-1A and MT-2A) in human lung cancer and cancer-surrounding tissues.
An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K-563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors.
We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study.
We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.