The current study revealed that Nrf2 contributes to pancreatic carcinogenesis in a way distinct from the chemoresistance of lung and esophagus, and that Nrf2 could be a novel therapeutic target of pancreatic cancer.
Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants.
Furthermore, this protein functions as a signaling hub for various signal transduction pathways, such as NF-κB signaling, apoptosis, and Nrf2 activation, whose dysregulation is associated with Paget disease of bone and tumorigenesis.
The lower cancer protection observed in NRF2 KO mice under calorie restriction (CR) suggests that most of the beneficial effects of CR on the carcinogenesis process are likely mediated by NRF2.
Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance.
Induction of NF-E2-related factor 2 (NRF2)-dependent detoxifying enzymes (e.g., NAD(P)H-quinone oxidoreductase 1 (NQO1)) is considered an important mechanism of protection against estrogen-associated carcinogenesis because they would facilitate removal of toxic estrogens.
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.
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.
The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes.
NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic 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.
Recent studies showed that NRF2 played significant roles in tumorigenesis and tumor progression, however no association and relationship between NRF2 expression and different clinical manifestation of solid tumor had been accurately evaluated.
Although it plays a protective role against tumorigenesis, emerging evidence has shown that the NRF2 pathway is frequently altered in different types of cancer, including lung cancer.
We constructed a canonical regulatory network for concerted modulation of Nrf2 and Nfkb1 involving several members of the mitogen-activated protein kinase (MAPK) family and present a putative model for concerted modulation of Nrf2 and Nfkb1 in inflammation/carcinogenesis.
Similarly, NF-E2-related factor 2 (Nrf2) also has two different roles, which makes it a key molecule for separating metal carcinogenesis into two different stages.