While association studies with genetic NRF2 polymorphisms supported a protective role for murine Nrf2 in oxidative airway diseases, somatic NRF2 mutations enhanced NRF2-ARE responses, and were favorable for lung carcinogenesis and chemoresistance.
Compound deletion of Atg7 and Nrf2 had no additive effect, suggesting that both genes modulate tumorigenesis by regulating oxidative stress and revealing a potential mechanism of autophagy-mediated tumor suppression.
We discovered that early tumorigenesis in Braf(V600E)-driven lung cancer is accelerated by autophagy ablation due to unmitigated oxidative stress, as observed with loss of Nfe2l2/Nrf2-mediated antioxidant defense.
We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in African-American esophageal squamous carcinogenesis.
We found that NQO1 is not essential for the beneficial effects of CR on glucose homeostasis, physical performance, metabolic flexibility, life-span extension, and (unlike our previously observation with Nrf2) chemical-induced tumorigenesis.
However, there is also a "dark side" to NRF2 function, as it has been found to enhance advanced stages of carcinogenesis in the lung and some other tissues.
Ingenuity Pathways Analysis (IPA) identified many cancer related pathways including PTEN, p53, Nrf2 and inflammatory signaling in UVB-irradiation induced carcinogenesis.
These data suggest that cross-talk between Nrf2 and RARalpha could markedly influence the sensitivity of cells to electrophiles and oxidative stressors and, as a consequence, to carcinogenesis.
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.
In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.
These findings indicate that the Nrf2-mediated suppression of apoptosis and promotion of autophagy contribute to nickel-induced transformation and tumorigenesis.
Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation.
We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis.