The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review

Abstract

BackgroundColorectal cancer is one of the most common cancers worldwide, and is influenced by the interplay of various factors, including a very strong genetic component. For instance, incorrect mitochondrial biogenesis is correlated with increased risk of developing colorectal cancer. Thus, it is important to understand the consequences of changes in both the expression and the correct function of the transcription factors that regulate mitochondrial biogenesis, namely NRF2.ObjectivesThe main objective of this paper is to characterise the relationship between NRF2 and colorectal cancer by compiling data from an exhaustive literature search.MethodsInformation was obtained by defining specific search terms and searching in several databases. After a strict selection procedure, data were tabulated and the relationships between articles were assessed by measuring heterogeneity and by constructing conceptual maps.Results and discussionWe found a general consensus in the literature that the presence of oxidizing agents as well as the inhibition of the NRF2 repressor Keap1 maintain NRF2 expression at basal levels. This predominantly exerts a cytoprotective effect on cells and decreases risk of colorectal cancer. However, if NRF2 is inhibited, protection against external agents disappears and risk of colorectal cancer increases. Interestingly, colorectal cancer risk is also increased when NRF2 becomes overexpressed. In this case, the increased risk arises from NRF2-induced inflammation and resistance to chemotherapy.ConclusionThe proper basal function of NRF2 and Keap1 are essential for preventing oncogenic processes in the colon. Consequently, any disruption to the expression of these genes can promote the genesis and progression of colon cancer.

Nitric Oxide Engages an Anti-inflammatory Feedback Loop Mediated by Peroxiredoxin 5 in Phagocytes

“…We identified Keap1 as a regulator of iNOS that was required for RNI production. Under basal conditions, Keap1 functions as a redox sensor by recruiting a ubiquitinconjugating complex to Nrf2, leading to constitutive degradation (Gonzalez-Donquiles et al, 2017; Itoh et al, 1997, 1999; Kobayashi et al, 2004). Upon oxidative stress, oxidative modification of key cysteine residues on Keap1 induces a conformational change that releases Nrf2, allowing it to undergo nuclear translocation and initiate transcription of the antioxidant program (Kobayashi et al, 2006; Nguyen et al, 2005; Zhang and Hannink, 2003).…”

Chemopreventive efficacy zingerone (4‐[4‐hydroxy‐3‐methylphenyl] butan‐2‐one) in experimental colon carcinogenesis in Wistar rats

“…NF‐ĸB inside nucleus modulates the transcription of wide variety of genes including proinflammatory mediators, such as COX‐2, i‐NOS, some cytokines chemokines, and adhesion molecules . Also, some earlier studies report that activation of NF‐κB facilitates transcriptional up‐regulation of COX‐2 and proinflammatory cytokines, such as TNF‐α, IL‐6, etc . DMH which generates lot of oxidants in colon tissue activates redox sensitive transcription factor NF‐κB .…”

“…However, during oxidative stress, Nrf2 is stabilized by detached from Keap1, and attached to cis‐elements called antioxidant response elements (AREs) . Nrf‐2 acts as a major regulator for the cellular defense against oxidative and electrophilic stresses by inducing enzymes that are involved in the detoxification and elimination of ROS, RNS, and electrophiles through conjugation and excretion . Studies conducted in the recent past reveal that in various human cancers, there is upregulation of Nrf2 expression.…”

“…Inflammation‐associated events are reported to be involved in the progress of human and DMH‐induced colon carcinogenesis . Considering the huge role of Nrf2 and NF‐κB it is implied that targeting by natural or alternative products could enhance the Nrf2/ARE pathways while suppress the NF‐κB/inflammatory pathways in colon cancer …”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…The list of all the proteins that interact with NRF2 in the human interactome is available online at http://sbi.imim.es/data/nrf2/. 352 formation underlining colon (Gonzalez-Donquiles et al, 2017) and breast (Lu et al, 2017) tumors.…”