http://orcid.org/0000-0001-6212-1797
Figures
Abstract
Background
Colorectal 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.
Objectives
The main objective of this paper is to characterise the relationship between NRF2 and colorectal cancer by compiling data from an exhaustive literature search.
Methods
Information 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 discussion
We 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.
Citation: Gonzalez-Donquiles C, Alonso-Molero J, Fernandez-Villa T, Vilorio-Marqués L, Molina AJ, Martín V (2017) The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review. PLoS ONE 12(5): e0177549. https://doi.org/10.1371/journal.pone.0177549
Editor: Sergei Grivennikov, Fox Chase Cancer Center, UNITED STATES
Received: January 18, 2017; Accepted: April 28, 2017; Published: May 18, 2017
Copyright: © 2017 Gonzalez-Donquiles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Colorectal cancer (CRC) is one of the most common cancers worldwide, and causes more than half a million deaths per year [1]. This type of cancer is a useful model for studying both carcinogenesis and tumour progression, as colonocytes follow a systematic process of proliferation, differentiation and transformation (adenoma to a carcinoma) [2]. CRC arises from stem cells in the colon [3], and its development is partly due to functional changes in the mitochondrial genome (mtDNA) [4].
Mitochondria play a crucial role in physiological processes, and their deregulation contributes to the genesis and progression of CRC. This is known as the Warburg effect, which consists of metabolic reprogramming that is characteristic of tumour processes. Thus, it is important that all genes involved in mitochondrial biogenesis are expressed according to a standard pattern. This process is highly coordinated and depends on the activity of several key proteins, including Nuclear Respiratory Factor 1 (NRF1) and Nuclear Respiratory Factor 2 (NRF2), which regulate the expression of respiratory chain proteins, and act as anti-oxidants [5].
NRF transcription factors control the functionality of the respiratory chain, the main pathway responsible for producing reactive oxygen species (ROS). ROS are extremely harmful for cellular micromolecules because they induce tumorigenesis through non-specific reactions with nucleic acids, proteins, and lipids [6].
NRF2 is considered to be a main defence mechanism and regulator of cell survival [7]. Under healthy conditions, NRF2 protects against tumorigenesis and cancer progression by attenuating genotoxic compounds that emerge both intrinsically and extrinsically. However, activation of the NRF2 defence response can promote the survival of both normal and cancer cells by creating an optimal environment for cell growth. Furthermore, NRF2 protects tumour cells from oxidative stress, chemotherapeutic agents, and radiotherapy, promoting tumour genesis and progression, and also metabolic reprogramming to anabolic pathways [8]. Fig 1 shows a simplified diagram of the mechanisms that can activate the transcription factor NRF2. NRF2 is sequestered by the inhibitor Keap1 and is transcriptionally inactive until Keap1 is dissociated by ROS. This dissociation allows NRF2 to form transcriptionally active complexes with other proteins, such as Mafs, and, after the transcription of cytoprotective and antioxidative genes, to remove ROS [9].
When ROS is acumulated, NRF2 is released from Keap1 and heterodimerizes with Small Mafs. In this way, it binds to AREs and the transcription of antioxidant and cytoprotective genes occurs.
In this study, we provide a qualitative systematic review to summarize the role of the NRF2 transcription factor. Our goal was to assess the effects of differential expression of NRF2 on CRC.
Methods
Literature search strategy
Literature searches and quality assessment were performed according to 'Guidance on the Conduct of Narrative Synthesis in Systematic Reviews' (S1 File) [10]. The search results were independently assessed by two individuals to minimize bias (one was an expert on this topic and the other had no knowledge of it).
Design of search strategies and use of Boolean operators
For each search, synonyms, related terms and spelling variations were taken into account, and Boolean operators were used to relate the terms. Searches were performed on eight different databases (PubMed, Scopus, Web of Science (WOS), Cochrane library, PysCinfo, PLoS One, Scielo and PubMedCentral (PMC)) using the following terms:
- 'Colorectal OR Colon OR Rectum OR Rectal' AND 'Cancer OR Carcinoma OR Tumor OR Tumour OR Neoplasm OR Cancer Cells' AND 'Mitochondrial Biogenesis OR Mitochondrial dysfunction OR Mitochondria OR Mitochondrion' AND 'NRF2 OR NFE2L2 OR Nuclear Respiratory Factor 2 OR Nuclear Factor Erythroid 2 Like 2'.
- 'Colorectal OR Colon OR Rectum OR Rectal' AND 'Cancer OR Carcinoma OR Tumor OR Tumour OR Neoplasm OR Cancer Cells' AND 'Warburg effect' AND 'NRF2 OR NFE2L2 OR Nuclear Respiratory Factor 2 OR Nuclear Factor Erythroid 2 Like 2'.
- 'Colorectal OR Colon OR Rectum OR Rectal' AND 'Cancer OR Carcinoma OR Tumor OR Tumour OR Neoplasm OR Cancer Cells' AND 'Oxidative phosphorylation OR OXPHOS OR Anaerobic glycolysis' AND 'NRF2 OR NFE2L2 OR Nuclear Respiratory Factor 2 OR Nuclear Factor Erythroid 2 Like 2'.
To retrieve optimal results when using the Scopus database, it was necessary to modify the search criteria. Thus, only the following more specific terms were used:
- 'CRC' AND 'NRF2 OR NFE2L2' AND 'Warburg'
- 'CRC' AND 'NRF2 OR NFE2L2' AND 'OXPHOS'.
We included only scientific reports written in English, and published after 2006, to obtain a current review of this issue. We collected articles using all combinations of search terms.
Selection process
The articles returned by the searches were manually screened to identify relevant articles to be included in this review: 1. Search results were integrated using informatics programs. We used the EndNote reference manager to remove duplicate articles. 2. Titles and abstracts were assessed to remove irrelevant articles. Only articles satisfying the following criteria were included: (i) the article considers CRC or other related diseases; (ii) the title of the article includes the word NRF2, or the name of another related gene; (iii) the article discusses the relationship between CRC and either mitochondrial biogenesis, OXPHOS or the Warburg effect. 3. The full texts of potentially relevant articles were retrieved and analysed to verify that they met the inclusion criteria.
Fig 2 shows a flow chart summarising each step in the search process. Reports that did not meet the inclusion criteria were excluded from the analysis. S1 Table lists the articles excluded in the last step of the search process.
This flow chart shows the process of selecting articles included in the qualitative systematic review.
Assessment of results
Tabulation.
We tabulated the following key data from each article: first author, publication year, organism/cell type, primary results and conclusion (S2 Table).
Heterogeneity.
To assess the heterogeneity of the selected articles, we analysed the following aspects: expression of NRF2, relationship to CRC, use of cell culture, NRF2 as a chemotherapeutic agent, apoptosis, the inflammatory process and mitochondrial function. To more easily view the specific characteristics of each article, and to evaluate the homogeneity among them, we represented each article in a stacked bar chart (Fig 3).
This graph evaluates if certain features are present in the articles included in this review.
Results
Article selection
The search described above identified relevant articles only in the Pubmed, Web of Science, and Scopus databases. Removing duplicated articles from these search results resulted in a total of 104 articles. We reviewed the titles of these articles and discarded those not related to our topic, reducing the number of articles to 82. We then reviewed the abstracts, further reducing the number of articles to 60. Finally, we reviewed the full text, and selected 40 articles for the review. This article selection process is summarized in Fig 2. Articles excluded in the last step are summarized in Supplementary Information 1.
Tabulation
Complete data from the 40 articles selected for this review are shown in Supplementary Information 2. All selected papers were published after 2006. The geographic settings of the studies vary, with nine from in the USA, nine from China, seven from Korea, four from Germany, four from Malaysia, three from India, two from Japan, and one each from the United Kingdom, Norway, and Australia. Most studies were based on human cancer cell lines. Only 13 studies used animal experimentation (mice), and four considered patients with ulcerative colitis or Crohn's disease. The most important results from the selected articles are shown in Supplementary Information 2. Titles, author and publication date of the included articles are shown in Table 1.
Building a concept map
To interconnect the ideas gathered from the articles included in this review, we constructed three conceptual maps focused on the expression of NRF2 and its effect on colon cancer. The first conceptual map was constructed on the basis of standard NRF2 gene expression and how it is influenced by various mechanisms or external agents. The second conceptual map explains the various effects and mechanisms of NRF2 overexpression, and the third shows the effects of NRF2 silencing or inhibition. Analysing all three conceptual maps sheds light onto how NRF2 expression affects CRC. As shown in Fig 4, correct expression of NRF2 prevent CRC in humans, while altered expression of this gene promotes tumour genesis and progression (Figs 5 and 6).
Oxidizing agents, the silencing of the Keap1 or the digitoflavonoids induce the expression of NRF2, decreasing the risk of CRC.
Constitutive activation of NRF2 promotes a serie of events that lead to an increased risk of CRC.
Inhibition or permanently silencing of NRF2 induce the formation of aberrant crypts and other typical processes related to the increased risk of CRC such as rectal bleeding or ulcerative colitis.
Discussion
The articles selected show that research on the role of NRF2 in CRC can be classified into three broad groups: i) those that analyse standard expression and observe a cytoprotective effect on CRC [11–17], and those that analyse variations in expression, either ii) overexpression or iii) inhibition, both leading to increased CRC risk. Below, we discuss the findings in each of these three lines of research.
The first concept map (Fig 4) shows the protective effect of induced expression of the NRF2 gene on CRC following a moderate accumulation of ROS due to specific external agents [18–22]. When NRF2 activates, it exerts a cytoprotective effect by decreasing genotoxic damage and promoting autophagy [23]. Sometimes, NRF2 expression leads to reduced cell proliferation and increased apoptosis of colon cancer cells [24–27]. In all cases, the authors observed the same final result, namely reduced risk of CRC. Another example of this behaviour was reported by Yang et al. (2014), in which digitoflavonoids were found to act upon p38 and to induce NRF2 target genes and antioxidants. They reported a reduction in both the number and size of tumours, as well as a decrease in the number of aberrant crypts, further pointing to a protective effect of NRF2 on CRC [28]. Therefore, expression of NRF2 and its target genes, such as glutathione synthase, likely play a crucial role in cytoprotective mechanisms against CRC [29–31].
In the studies mentioned up to this point, NRF2 expression is directly induced by the external agents. However, NRF2 expression can also be promoted indirectly by other mechanisms, via the repressor Keap1. For example, Jung and Kwak, 2013 silenced Keap1 and found that induction of NRF2 promoted the expression of AKR members, which are involved in the detoxification process, leading to reduced risk of CRC [32]. In another study, Lu et al., 2016 used an inhibitor of its interaction with NRF2, CPUY192018, and observed that activated NRF2 acted as a protective factor upon exposure to DSS, decreasing CRC risk [33].
In all of these cases, standard NRF2 expression levels function as a protective factor against CRC by providing cytoprotection and by activating antioxidant target genes. These results are corroborated by the review by Pandurangan and Esa, (2014) and Pandurangan et al (2014a, 2014b), who also support the idea that expression of NRF2 decreases the risk of CRC [12, 29, 50].
As shown in the second concept map (Fig 5), several studies have reported that NRF2 overexpression increases risk of CRC. This overexpression can occur for a number of reasons, including constitutive mutations in the Keap1 repressor gene or in the NRF2 gene itself. Stachel et al. (2014) found that excessive levels of ROS induced overexpression of NRF2, leading to inflammation of the colon tissue and promoting tumorigenesis [34]. In another study, Sebens et al. (2011) reported overexpression of NRF2 in tissues exposed to inflammatory macrophages, and a simultaneous increase in the activity of proteosomal genes, leading to reduced apoptosis and uncontrolled proliferation. This in turn results in greater risk of CRC [35]. Other authors have observed similar results when NRF2 is overexpressed as a consequence of silencing, or as a result of epigenetic changes in this gene [36–38, 51]. Another way to induce overexpression of NRF2 is using chemical compounds. Kim et al. (2011) found that T-BHQ-induced overexpression of NRF2 resulted in increased O2 consumption, which is correlated with higher HIF-1α and VEGF signalling, which in turn directly increases angiogenesis and tumour growth [6]. Therefore, as mentioned above, overexpression of the NRF2 gene is closely linked to increased risk of CRC [39, 40]. In this case, CRC risk can increase by promoting colonic inflammation, decreasing apoptosis, or promoting angiogenesis and uncontrolled cell proliferation.
Notably, NRF2 overexpression has also been linked to increased resistance to the chemotherapeutic agent 5-FU via the activity of demethylases and methyltransferases. In addition to the increase risk of CRC, this implies a poorer response to treatments based on this agent. [37,41].
The third concept map (Fig 6) shows that inhibited expression of NRF2 also has consequences for this type of cancer, since one of NRF2’s functions is to protect against damaging and carcinogenic substances [42,43]. Various studies highlight the role of NRF2 on CRC via its inhibition. Li et al. (2008) related Nrf2 inhibition with increased risk of CRC [44]. Yokoo et al. (2016) found that silencing Nrf2 resulted in decreased expression of the COX2 gene, leading to an increase in the number of aberrant crypts, resulting in the formation of adenoma, adenocarcinoma and ultimately CRC [36]. Other studies have compared the effects of silencing the Nrf2 gene in mice and exposing them to treatments that induce ulcerative colitis (DSS) or colon carcinogenesis (AOM) [45–46]. Nrf2 knockout mice with ulcerative colitis suffer prolapse, rectal bleeding, inflammation, and as in the previous case, show an increase in the number of aberrant crypts. Together, these symptoms contribute to the development of CRC. This information is corroborated by reviews from Saw and Kong in 2011 [47] and Cheung et al. in 2014 [48].
Analysing the behaviour of this gene, not at a single time point, but throughout the various stages, Chang et al. (2013) suggested that the differential expression profile of NRF2 in tumour versus normal tissue could be an interesting new target for CRC treatment [49]. Similarly, Arlt et al. (2009) observed that NRF2 expression is beneficial during early stages, but can contribute to tumorigenesis in the colon at later stages [43]. These data are also supported by Menegon et al (2016) and Sporn M and Liby K (2012), who described NRF2 not only as an oncogene but also as a tumour suppressor gene [52,53]. In addition, few studies have analysed the role of Single Nucleotide Polymorphisms (SNPs) in this gene and its promotor, although Yokoo et al. (2016) suggested that some SNP alleles in the NRF2 gene could increase CRC risk based on previous studies of these polymorphisms and the risk of ulcerative colitis [36].
Finally, another important factor is the type of cell used in the studies included in this review. Most of the articles focus on colon stem cells, which need more energy and therefore require greater expression of NRF2 to obtain the necessary ATP for proliferation, migration and differentiation, such that altered expression of NRF2 increases genetic instability leading to increased CRC risk. In vivo, these cells migrate to the apical part of the crypt and become mature epithelial cells, and altered expression of NRF2 during migration and differentiation, will lead to an accumulation of mutations that promote tumorigenesis due to absence of cytoprotection. Thus, NRF2 function is probably essential in both the stem cells of the colon and in mature epithelial cells [54].
Although we searched several databases using an exhaustive list of relevant terms, our study has some limitations. We only selected articles published in English, which could result in selection bias. In addition, the use as search terms such as oxidative phosphorylation, mitochondria or Warburg effect, could limit the selection of articles that relate NRF2 to colorectal cancer, although searches performed without these concepts in several databases did not return any additional relevant articles.
In conclusion, it is clear that the NRF2 transcription factor has a very complex role in the cell, and that its expression can be strongly affected by external agents. Any disruption of its standard expression, be it overexpression or silencing, can promote the genesis and progression of CRC. Further studies are needed to clarify the role of NRF2, particularly to analyse the role of various SNPs that could generate variability in the expression and function of the protein in humans, as well as to study the pathways regulated by this gene, and possible interactions with environmental and behavioural factors, although such studies require large sample sizes.
Supporting information
S1 File. Guidance on the Conduct of Narrative Synthesis in Systematic Reviews.
https://doi.org/10.1371/journal.pone.0177549.s001
(PDF)
S1 Table. Excluded reports which not keep the inclusion criteria.
https://doi.org/10.1371/journal.pone.0177549.s003
(DOCX)
Acknowledgments
I would like to recognize the advice and corrections given by Silvia Gutiérrez Cosio, Fernanda de Souza Teixeira and Verónica Davila Batista.
Author Contributions
- Conceptualization: CGD.
- Data curation: CGD AJM LVM.
- Formal analysis: CGD JAM TFV.
- Investigation: CGD JAM.
- Methodology: CGD JAM TFV LVM AJM VM.
- Project administration: VM.
- Resources: CGD.
- Software: CGD.
- Supervision: AJM VM.
- Validation: JAM TFV.
- Visualization: CGD.
- Writing – original draft: CGD AJM.
- Writing – review & editing: CGD JAM TFV LVM AJM VM.
References
- 1. Siegel R, Naishadham D, & Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63(1), 11–30. pmid:23335087
- 2. R , Giulivi C. Coordination of nuclear- and mitochondrial-DNA encoded proteins in cancer and normal colon tissues. Biochim Biophys Acta—Bioenerg. 2006;1757(5–6):618–23.
- 3. Greaves LC, Preston SL, Tadrous PJ, Taylor RW, Barron MJ, Oukrif D, et al. Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci U S A. 2006;103(3):714–9. pmid:16407113
- 4. Habano W, Sugai T, Yoshida T, Nakamura S ichi. Mitochondrial gene mutation, but not large-scale deletion, is a feature of colorectal carcinomas with mitochondrial microsatellite instability. Int J Cancer. 1999;83(5):625–9. pmid:10521798
- 5. Boland ML, Chourasia AH, Macleod KF. Mitochondrial Dysfunction in Cancer. Front Oncol. 2013;3:1–28
- 6. Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Mie Lee Y, et al. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α Cancer Res. 2011;71(6):2260–75. pmid:21278237
- 7. Jaramillo M, Zhang D. The emerging role of the NRF2–Keap1 signaling pathway in cancer. Genes Dev. 2013;27:2179–91. pmid:24142871
- 8. Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of NRF2 in cancer. Pharmacol Res. 2008;(58)(5–6):262–270. pmid:18838122
- 9. Rodríguez-Ramiro I, Ramos S, Bravo L, Goya L, Martín MÁ. Procyanidin B2 induces NRF2 translocation and glutathione S-transferase P1 expression via ERKs and p38-MAPK pathways and protect human colonic cells against oxidative stress. Eur J Nutr. 2012; 51: 881–92. pmid:22042007
- 10.
Popay J, Roberts H, Sowden A, Petticrew M, Arai L, Rodgers M, et al. Guidance on the conduct of narrative synthesis in systematic reviews. A product from the ESRC methods programme Version. 2006; 1, b92.
- 11. Bat-Chen W, Golan T, Peri I, Ludmer Z, Schwartz B. Allicin purified from fresh garlic cloves induces apoptosis in colon cancer cells via NRF2. Nutr Cancer. 2010;62(7):947–57. pmid:20924970
- 12. Pandurangan AK, Esa NM. Luteolin, a bioflavonoid inhibits colorectal cancer through modulation of multiple signaling pathways: A review. Asian Pacific J Cancer Prev. 2014;15(14):5501–8.
- 13. Kim H, Kim W, Yum S, Hong S, Oh J, Lee J, et al. Free Radical Biology and Medicine Caffeic acid phenethyl ester activation of NRF2 pathway is enhanced under oxidative state : Structural analysis and potential as a pathologically targeted therapeutic agent in treatment of colonic in fl ammation. Free Radic Biol Med. 2013;65:552–62
- 14. Pandurangan AK, Saadatdoust Z, Hamzah H, Ismail A. Dietary cocoa protects against colitis‐associated cancer by activating the NRF2/Keap1 pathway. BioFactors. 2015; 41(1), 1–14. pmid:25545372
- 15. Li Y, Shen L, Luo H. International Immunopharmacology Luteolin ameliorates dextran sulfate sodium-induced colitis in mice possibly through activation of the NRF2 signaling pathway. Int Immunopharmacol. 2016;40:24–31.
- 16. Chiou YS, Tsai ML, Nagabhushanam K, Wang YJ, Wu CH, Ho CT, et al. Pterostilbene is more potent than resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (NRF2)-mediated antioxidant signaling pathway. J. Agric. Food Chem 2011; 59(6), 2725–33. pmid:21355597
- 17. Trivedi PP, Jena GB. Role of a -lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice : Studies on inflammation, oxidative stress, DNA damage and fibrosis. FOOD Chem Toxicol. 2013; 59, 339–55. pmid:23793040
- 18. Pettersen K, Monsen VT, Hakvåg Pettersen CH, Overland HB, Pettersen G, Samdal H, et al. DHA-induced stress response in human colon cancer cells—Focus on oxidative stress and autophagy. Free Radic Biol Med. 2016;90:158–72. pmid:26585906
- 19. Myers JN, Schaffer MW, Korolkova OY, Williams AD, Gangula PR, M’Koma AE. Implications of the colonic deposition of free hemoglobin-alpha chain: a previously unknown tissue by-product in inflammatory bowel disease. 2014; 20(9), 1530–47.
- 20. Xi M, Sun Z, Sun H, Jiang J, Wang Y, Zhang M. 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent NRF2/ARE inducers in human cancer cells and AOM-DSS treated mice. J. Med. Chem. 2013; 56(20), 7925–38 pmid:24053646
- 21. Park EJ, Lim JH, Nam SI, Park JW, Kwon TK. Rottlerin induces heme oxygenase-1 (HO-1) up-regulation through reactive oxygen species (ROS) dependent and PKC δ-independent pathway in human colon cancer HT29 cells. Biochimie. 2010; 92(1), 110–15. pmid:19833168
- 22. Jang HJ, Hong EM, Kim M, Kim JH, Jang J, Park SW, et al. Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (NRF2) activation through ERK and PI3K/Akt pathway in colon cancer. Oncotarget.2016; 7(29).
- 23. Trivedi PP, Jena GB, Tikoo KB, Kumar V. Melatonin Modulated Autophagy and NRF2 Signaling Pathways in Mice With Colitis-Associated Colon Carcinogenesis. Mol Carcinog. 2016 Mar;55(3):255–67. pmid:25598500
- 24. Xu DG, Lv W, Dai CY, Zhu FF, Xu GH, Ma ZJ, et al. 2-(Pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3-diynyl) thiophene induces apoptosis through reactive oxygen species-mediated JNK activation in human colon cancer SW620 cells. Anat Rec. 2015;298(2):376–85.
- 25. Tan BL, Norhaizan ME, Huynh K, Yeap SK, Hazilawati H, Roselina K. Brewers ‘ rice modulates oxidative stress in azoxymethane- mediated colon carcinogenesis in rats. 2015;21(29):8826–35.
- 26. Volonte D, Liu Z, Musille PM, Stoppani E, Wakabayashi N. Inhibition of nuclear factor-erythroid 2 –related factor (NRF2) by caveolin-1 promotes stress- induced premature senescence. Mol Bio Cell. 2013; 24(12), 1852–62.
- 27. Kruse ML, Friedrich M, Arlt A, Röcken C, Egberts JH, Sebens , et al. Colonic Lamina Propria Inflammatory Cells from Patients with IBD Induce the Nuclear Factor-E2 Related Factor-2 Thereby Leading to Greater Proteasome Activity and Apoptosis Protection in Human Colonocytes. Inflamm Bowel Dis. 2016; 22(11), 2593–2606. pmid:27661668
- 28. Yang Y, Cai X, Yang J, Sun X, Hu C, Yan Z, et al. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing NRF2 signaling pathway and inhibition of inflammation. Mol Cancer. 2014;13:48. pmid:24602443
- 29. Pandurangan AK, Kumar S, Sadagopan A, Dharmalingam P, Ganapasam S. Luteolin, a bioflavonoid inhibits Azoxymethane-induced colorectal cancer through activation of NRF2 signaling. Toxicol. Mech. Meth. 2014;6516(1):13–20.
- 30. Wondrak GT, Villeneuve NF, Lamore SD, Bause AS, Jiang T, Zhang DD. The cinnamon-derived dietary factor cinnamic aldehyde activates the NRF2-dependent antioxidant response in human epithelial colon cells. Molecules.2010; 15(5), 3338–3355. pmid:20657484
- 31. Li CQ, Kim MY, Godoy LC, Thiantanawat A, Trudel LJ, Wogan GN. Nitric oxide activation of Keap1/NRF2 signaling in human colon carcinoma cells. Proc Natl Acad Sci U S A. 2009;106(34):14547–51. pmid:19706542
- 32. Jung K-A, Kwak M-K. Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells. Oxid Med Cell Longev. 2013;2013:1–16.
- 33. Lu M-C, Ji J-A, Jiang Y-L, Chen Z-Y, Yuan Z-W, You Q-D, et al. An inhibitor of the Keap1-NRF2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep. Nature Publishing Group; 2016;6:26585.
- 34. Stachel I, Geismann C, Aden K, Deisinger F, Rosenstiel P, Schreiber S, et al. Modulation of nuclear factor E2-related factor-2 (NRF2) activation by the stress response gene immediate early response-3 (IER3) in colonic epithelial cells: A novel mechanism of cellular adaption to inflammatory stress. J Biol Chem. 2014;289(4):1917–29. pmid:24311782
- 35. Sebens S, Bauer I, Geismann C, Grage-Griebenow E, Ehlers S, Kruse ML, et al. Inflammatory macrophages induce NRF2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection. J Biol Chem. 2011;286(47):40911–21. pmid:21990354
- 36. Yokoo Y, Kijima A, Ishii Y, Takasu S, Tsuchiya T, Umemura T. Effects of NRF2 silencing on oxidative stress-associated intestinal carcinogenesis in mice. Cancer Med. 2016;
- 37. Kang KA, Piao MJ, Kim KC, Kang HK, Chang WY, Park IC, et al. Epigenetic modification of NRF2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation. Cell Death Dis. 2014; 5:e1183. pmid:24743738
- 38. Zhao XQ, Zhang YF, Xia YF, Zhou ZM, Cao YQ. Promoter demethylation of nuclear factor-erythroid 2-related factor 2 gene in drug-resistant colon cancer cells. Oncol Lett. 2015; 10(3), 1287–92. pmid:26622665
- 39. Hu T, Yao Y, Yu S, Guo H, Han L, Wang W, et al. Clinicopathologic significance of CXCR4 and NRF2 in colorectal cancer. Int J of Biomed Res. 2013;27(4):283–90.
- 40. Ji L, Wei Y, Jiang T, Wang S. Correlation of NRF2, NQO1, MRP1, cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival. Int J Clin Exp Pathol. 2014;7(3):1124–31. pmid:24695690
- 41. Kang KA, Piao MJ, Ryu YS, Kang HK, Young W. Interaction of DNA demethylase and histone methyltransferase upregulates NRF2 in 5-fluorouracil-resistant colon cancer cells. Oncotarget. 2016
- 42. Ishaq M., Evans M. D., & Ostrikov K. K.. Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2–ASK1 apoptosis pathways and oxidative stress is mitigated by Srx–NRF2 anti-oxidant system. Biochim Biophys Acta. 2014; 1843(12), 2827–2837. pmid:25173814
- 43. Arlt A, Bauer I, Schafmayer C, Tepel J, Mu SS, Brosch M, et al. Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (NRF2). Oncogene. 2009; 28(45), 3983–96. pmid:19734940
- 44. Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, et al. Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis. Biochem. Pharmacol. 2008; 76(11), 1485–89. pmid:18694732
- 45. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN. NRF2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 2006;66(24):11580–4. pmid:17178849
- 46. Osburn WO, Karim B, Dolan PM, Liu G, Yamamoto M, Huso DL, et al. Increased colonic inflammatory injury and formation of aberrant crypt foci in NRF2-deficient mice upon dextran sulfate treatment. Int J Cancer. 2007;121(9):1883–91. pmid:17631644
- 47. Saw CLL, Kong A-NT. Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. Expert Opin Ther Targets. 2011; 15(3), 281–95. pmid:21261563
- 48. Cheung KL, Lee JH, Khor TO, Wu TY, Li GX, Chan J., et al. NRF2 knockout enhances intestinal tumorigenesis in Apcmin/+ mice due to attenuation of anti-oxidative stress pathway while potentiates inflammation. MOL CARCINOGEN. 2014; 53(1), 77–84.
- 49. Chang LC, Fan CW, Tseng WK, Chen JR, Chein HP, Hwang CC, et al. Immunohistochemical study of the NRF2 pathway in colorectal cancer: NRF2 expression is closely correlated to Keap1 in the tumor and Bach1 in the normal tissue. Appl Immunohistochem Mol Morphol. 2013. 21(6), 511–517. pmid:23455180
- 50. Pandurangan AK, Esa NM. Dietary non-nutritive factors in targeting of regulatory molecules in colorectal cancer: An update. Asian Pacific J Cancer Prev. 2013;14(10):5543–52.
- 51. Yao J, Zhao L, Zhao Q, Zhao Y, Sun Y, Zhang Y, et al. NF-κB and NRF2 signaling pathways contribute to wogonin-mediated inhibition of inflammation-associated colorectal carcinogenesis. Cell Death Dis. 2014;5:1283.
- 52. Menegon S, Columbano A, Giordano S. The Dual Roles of NRF2 in Cancer. Trends Mol Med. 2016; 22: 578–93. pmid:27263465
- 53. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012; 12: 564–71. pmid:22810811
- 54. D'Errico I, Salvatore L, Murzilli S, Sasso GLO, Latorre D, Martelli N, et al. Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate. Proc. Natl. Acad. Sci. USA. 2011; 108(16), 6603–08. pmid:21467224