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Emerging roles of Nrf2 signal in non-small cell lung cancer

Journal of Hematology & Oncology volume 9, Article number: 14 (2016) Cite this article

Abstract

Non-small cell lung cancer (NSCLC) causes considerable mortality in the world. Owing to molecular biological progress, treatments in adenocarcinoma have evolved revolutionarily while those in squamous lung cancer remain unsatisfied. Recent studies revealed high-frequency alteration of Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-like factor 2 (Keap1/Nrf2) pathway within squamous lung cancer, attracting researchers to focus on this particular pathway. In NSCLC patients, deregulated Nrf2 signal is recognized as a common feature at both DNA and protein level. Emerging associations between Nrf2 and other pathways have been elucidated. MicroRNA was also implicated in the regulation of Nrf2. Agents activating or antagonizing Nrf2 showed an effect in preclinical researches, reflecting different effects of Nrf2 during tumor initiation and progression. Prognostic evaluation demonstrated a negative impact of Nrf2 signal on NSCLC patients’ survival. Considering the importance of Nrf2 signal in NSCLC, further studies are required in the future.

Background

Non-small cell lung cancer (NSCLC) remains to be the leading cause of tumor-related mortality [1, 2]. Among main pathological types of NSCLC, identification of epidermal growth factor receptor (EGFR) mutation [3, 4], echinoderm microtubule-associated protein-like anaplastic lymphoma kinase (EML4-ALK) fusion [5, 6], and other genetic alterations bring revolutionary improvements to the treatment of advanced lung adenocarcinoma. Other genetic/epigenetic alterations, including long non-coding RNAs HOTAIR [7] and GAS5 [8] and potential oncogenes Notch1 [9], alpha-enolase [10], and NLK [11] are also contributed to the progression of NSCLC. Biomarker-guided strategy has been demonstrated to improve chemotherapy response for NSCLC patients [12]. However, conventional chemotherapy and radiotherapy continue to be the standard regime for squamous lung cancer patients who lose their chances to surgery [13].

To better understand the genetic feature of squamous cell lung cancer, The Cancer Genome Atlas (TCGA) network attempted to unveil the genomic alterations in this common pathological type through comprehensive approaches [14]. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-like factor 2 (Nrf2)/Cullin3 pathway alterations occur in a third of squamous cell lung cancer according to TCGA discoveries. Another study conducted by Kim et al. indicated that the proportion in East Asian population was as high as 39.4 % [15]. Keap1 negatively regulates intracellular Nrf2 protein abundance and represses the activation of Nrf2 signal [16]. Gene knockout mice model and clinical studies proved that Nrf2 signal is crucial in the initiation and progression of lung cancer. Nrf2 signal exerts a favorable chemopreventive influence on mice teratologenic tests by promoting carcinogen elimination, suggesting its anti-initiation effects [17]. Clinical observations also suggested a correlation between enhanced Nrf2 signal activities and worse treatment outcomes [18]. Expressions of various cytoprotective genes are upregulated when Nrf2 signal activates to increase pro-survival potential under endogenous or exogenous stress stimulation [19]. These genes are involved in multiple biological processes including glutathione synthesis, purine denovo synthesis, glycometabolism, drug-pump system, and serine synthesis [20–23]. Furthermore, there are crosstalks between Nrf2 and other oncogenic signal pathways such as phosphatidylinositol 3-kinase (PI3K) [24], Kirsten retrovirus-associated DNA sequence (K-ras) [25], and Notch [26]. This minireview will mainly focus on emerging relevance between Nrf2 signal and NSCLC to give a glimpse of what have been achieved in this realm.

Nrf2 and Keap1 expression in NSCLC

Tobacco exposure is considered to be the principal cause of non-small cell lung cancer [27]. As a major carcinogen for squamous cell lung cancer, cigarette exposure can activate the oxidant stress response [28]. Sekine et al. analyzed gene expression of H292 (human lung mucoepidermoid cancer cell) and found that after exposure to total particular matter (TPM) of tobacco leaf, Nrf2-mediated oxidative stress response was significantly activated [29]. Hu et al. examined Nrf2 sequences of 103 patients with NSCLC and discovered that the Nrf2 mutation rate in ever-smokers was significantly higher than that in never-smokers [30]. In accordance with Hu, Sasaki et al. sequenced Nrf2 in 262 surgically resected lung tumors and confirmed that Nrf2 mutation were more common in squamous lung cancer and smokers [31]. Genomic analysis also showed approximately 30 % of squamous lung cancer harbor alterations within the Keap1/Nrf2 pathway [14, 15].

On the other hand, Singh et al. demonstrated that deletion of Keap1 locus (19p13.2) recurrently occurred in NSCLC, which might increase the nuclear accumulation of Nrf2 and reduce tumor’s sensitivity to chemotherapy [32]. In addition, Muscarella et al. discovered that 22 in 47 NSCLC exhibited a hypermethylation of CpG in Keap1 promoter [33].

At protein level, several studies have shown that Nrf2 was frequently deregulated in NSCLC tumor tissues [18, 34]. Solis et al. demonstrated that nuclear Nrf2 abundance was higher in squamous cell lung cancer than in adenocarcinoma [35]. Keap1 absent or low in abundance were more common in adenocarcinoma. And it was indicated that nuclear Nrf2 abundance associated with worse progress-free survival in squamous lung cancer patients treated by platinum-based adjuvant regimen.

Increasing numbers of microarray assays have been conducted to profile NSCLC genomic features, which provide an opportunity to link novel target genes with clinicopathological characteristics. Cescon et al. reanalyzed squamous lung cancer’s expression profile of TCGA and two other datasets to identify a gene list associated with Nrf2 activation, and eventually separated squamous lung cancer into activated and wild-type groups [36]. This molecular signature classification was reproducible and could help predict survival within certain studies to some extent.

Interactions between Keap1 and Nrf2

Keap1/Nrf2 pathway modulates redox homeostasis in mammal cells [37]. Nrf2 contains a basic-leucine zipper structure and belongs to the Cap’n’Collar transcription factors [38]. By linking its ETGE and DLG motifs with dimerized Kelch domain, a model called “hinge and latch” is fixed to the actin cytoskeleton [39]. As a negative regulator of Nrf2, Keap1 assembles Cullin3 to form Cullin-E3 ligase complex which degrades Nrf2 protein via ubiquitin-proteasome route [34]. When electrophiles and xenobiotics appear intracellularly, bounds between Nrf2 and Keap1 are counteracted [40]. Nrf2 protein then evades degradation and translocates from cytoplasm to nucleus under the direction of a bipartite nuclear localization signal (NLS) [41, 42], thereby dimerizing with c-Jun [43] and small Maf [44] before binding to the antioxidant response element (ARE) [45]. It has been demonstrated that amino residuals on Keap1 protein directly react with electrophiles and xenobiotics to perceive intracellular stress condition [46–49]. Table 1 summarized Keap1 amino residuals involved in the activation of Nrf2. Figure 1 illustrated tertiary structure of Broad complex, Tramtrack, and Bric à brac (BTB) domain of Keap1.

Table 1 Summary of Keap1 amino residuals involved in the activation of Nrf2 signal
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Fig. 1
figure 1

Corresponding amino residuals within Keap1 BTB domain on tertiary structure. Amino residues marked in different colors with arrows showed its serial number on peptide chain. Simulation of tertiary structure was constructed using PDB file of 4CXI produced by Cleasby et al. [110]. PyMOL Molecular Graphics System was used to present this domain

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Nrf2 downstream genes generally contain a conserved sequence in the promoter region, which binds with Neh4 and Neh5 domain of Nrf2 [50]. ARE exists in a variety of intracellular antioxidant genes such as glutamate-cysteine ligase modifier subunit (Gclm), NAD(P)H quinone oxidoreductase 1 (Nqo1), glutathione S-transferase (Gst), heme oxygenase-1 (Ho-1) [51]. These genes encode phase II metabolic enzymes which mainly participate in the defense of drugs and reactive oxygen species (ROS) [52]. Gclm is a rate-limiting enzyme involved in the synthesis of glutathione [38]. Gst is best known for its ability to catalyze the conjugation of GSH with xenobiotics substrate, which can help in detoxification. Nqo1 catalyzes the process of NAD(P)H dehydrogenation to NAD(P)+. After the dehydrogenation, a quinone turns into a hydroquinone which could be easily eliminated in water-soluble form [53]. Different from the above three genes, Ho-1 plays an important role in attenuating inflammatory response and preventing cell apoptosis. Ho-1 could bind to gene promoter as well as directly interact with inflammation factor Stat3 besides its heme degradation function [54]. Dey et al. demonstrated that Ho-1 prevented anoikis (a special form of apoptosis) and promote metastasis of colorectal fibrosarcoma cells [55]. However, Ho-1 exhibited an unusual antitumor effect in mucoepidermoid lung carcinoma by down-regulation of matrix metalloproteinase [56, 57]. In addition, Multidrug resistance-associated protein 1 (MRP1) contains two potential AREs which may interact with Nrf2 when its activator tertiary butylhydroquinone (t-BHQ) is administrated to small cell lung cancer cell line H69 [58].

Recently, the involvement of Nrf2 has also been recognized in mitochondrial physiology [59]. Through producing more substrates (NADH and FADH2) for respiration and augmenting aliphatic acid oxidation, Nrf2 influences mitochondrial activity [60]. Keap1/Nrf2 signal regulated both mitochondrial and cytoplasmic ROS production through NADPH oxidizing in cortical neurons and glial cells [61]. Besides, Nrf2 affected other physiological characteristics of mitochondrion including membrane potential [62], membrane integrity [63], and biogenesis [64].

Emerging gene crosstalks with Nrf2 signal

Classical oncogenic pathways such as PI3K and K-ras have been reported to have an impact on Nrf2 function, as well as some other well-known transcription factors such as Bach1, estrogen receptor(ER)-α, NF-kappa B, and HIF-1α.

Nrf2 and PI3K

PI3K signal pathway is a classical oncogenic gene as it enhances tumor cell growth, viability, and metabolism [65]. PI3K inhibitor NVP-BKM120 reduced expression of Nrf2 in squamous lung cancer cells [24]. However, the mechanism involved has not been elucidated. Activated PI3K signal increased Nrf2 accumulation in nuclear [21], thereby enhancing multiple biological processes including de novo purine nucleotides synthesis, glutamine metabolism, and pentose phosphate pathway. Among these processes, enzymes involved in the pentose phosphate pathway provided substrates for purine synthesis and glutamine metabolism to promote cell proliferation and cytoprotection.

Nrf2 and K-ras

K-ras gene mutations repeatedly occur at a proportion of 20~30 % in NSCLC [66]. Mutated K-ras proteins cause aberrant activation of downstream signal and confer to cancer cells’ resistance and survival. Lung adenocarcinoma patients harboring K-ras mutation tended to be chemoresistant and had dismal prognosis [67, 68]. Tao [25] and DeNicola et al. [69] identified that constitutive expression of K-ras mutation G12D enhanced Nrf2 mRNA levels. Promoter analysis showed that a TPA response element (TRE) located in exon1 of Nrf2 was activated by K-ras. Remarkably, Satoh et al. modeled the process of lung carcinogenesis with urethane and found that Nrf2−/− mice were rarely associated with K-ras mutation [17]. They also established Nrf2 prevented tumor initiation but promoted progression in different phases during carcinogenesis.

Nrf2 and Bach1

Bach1, a nuclear transcription factor, was reported to co-localize with Nrf2 in nucleus in HepG2 cells and attenuate the binding between Nrf2 and ARE [70]. This negative regulation of Bach1 resulted in the balance of redox within cells. In earlier research of Sun et al., evidences revealed that the repression was mediated by Ho-1 and its substrates heme [71]. Reichard et al. found that during arsenite-mediated oxidative stress, Bach1 inactivation allowed Nrf2 binding to Ho-1 promoter and elevating Ho-1 mRNA [72].

Nrf2 and ER-α

Estrogen receptor (ER) is tightly related to the development and biological behavior of multiple cancers. Researches suggested that ER-α repressed the activity of Nrf2 and the transcription of phase II metabolic enzymes [73, 74]. Further exploration revealed that this repression resulted from the interaction between ER-α and Nrf2 and required the coordination of ER ligand 17-estradiol [73].

Nrf2 and Sirt1

Acetylation of amino residuals typically stabilized Nrf2 proteins and prevented it from degradation [75]. Sirt1 is an enzyme primarily engaged in catalyzing protein deacetylation in nucleus [76]. Kawai et al. noticed that CREB-binding protein (CBP) mediated acetylation of Nrf2 and gave rise to its target gene mRNA, while Sirt1 deacetylated Nrf2 and vice versa [77]. By constructing mutations of pK588Q and pK591Q, they unveiled an indispensible role of lysine residuals on Nrf2 in the process of Sirt1 regulation.

Nrf2 and NF-kappa B

Inflammatory response activation always occurs with elevation of ROS [78]. As a classical pro-inflammatory factor, NF-kappa B has been implicated in the regulation of Nrf2. Liu et al. found that NF-kappa B subunit p65 specifically deprived CBP from Nrf2, leading to inhibition of Nrf2 and its downstream genes [79]. Oppositely, Rushworth et al. recently reported that NF-kappa B subunits p50 and p65 promoted transcription of Nrf2 by binding to a kappa B site in acute myeloid leukemia, and conferred to resistance to cytotoxic treatment [80]. These findings suggested distinct patterns of crosstalk between NF-kappa B and Nrf2 in different cell contexts.

Nrf2 and HIF-1α

HIF-1α is a key transcription factor mainly monitoring oxygen homeostasis. Under hypoxic condition, HIF-1α escapes from degradation mediated by prolyl hydroxylase domain proteins and augments downstream gene expression [81]. In human endothelial cells, Loboda et al. discovered that induction of HIF-1α attenuated Nrf2-dependent expression of IL-8 and Ho-1 [82]. Thereafter, investigator in the realm of colon cancer has identified Nrf2 as an important factor in activating HIF-1α. Kim et al. found that stably inhibiting Nrf2 signal in colon cancer cell led to attenuated HIF-1α activation, subsequently causing a reduction of blood vessel formation and vascular endothelial growth factor expression [83].

Nrf2 and Notch1

Notch family consists of a series of intracellular signal mediators with highly conserved domain [84, 85]. It was reported that Notch1 and Notch3 expressions were closely associated with NSCLC patients’ progression and prognosis [86]. Wakabayashi et al. found Notch signal activation upregulated Nrf2 and cytoprotective genes in mouse liver [87]. They also demonstrated that Notch intracellular domain (NICD) assembled to the Rbpjκ site of Nrf2 promoter, leading to the activation of Nrf2 signal. Inversely, Nrf2 activation induced by ROS enhanced the Notch pathway, thus promoting airway basal stem cells’ self-renewal [88]. Paul et al. identified a putative ARE within Notch1 promoter [88]. More recently, Zhao et al. discovered that ionizing radiation exposure induced Nrf2 activation and knockdown of Nrf2 attenuated Notch1 expression following ionizing radiation [89]. The evidences above indicated a mutual promotion model for the crosstalk of Nrf2 and Notch1.

MicroRNAs associated with Nrf2

MicroRNA-related mechanisms play a critical role in the regulation of Nrf2. Several studies have identified microRNAs which directly decreased Nrf2 mRNA in breast and esophageal cancer. miR-28 targeted 3′-untranslated region (UTR) of Nrf2 to exhibit a significant silencing effect in breast cancer [90]. In addition, by screening reporter-coupled microRNA library, Yamamoto et al. discovered that miR-507, miR-634, miR-450a, and miR-129-a directly targeted Nrf2 to mediate mRNA degradation in esophageal cancer [91]. Besides, miR-200a was reported to associate with and trim Keap1 mRNA and thus increased the levels of Nrf2 protein and downstream transcripts [92].

Nrf2 also modulates microRNAs to mediate pro-survival processes. In lung cancer, Singh et al. further examined Nrf2’s effects on the pentose phosphate pathway and tricarboxylic acid cycle, discovering that activation of Nrf2 reduced miR-1 and miR-206 expression and resulted in elevation of metabolic gene expression in the pathway [93]. Chemotherapy induces apoptosis in not only cancer cells but also normal tissue. Joo et al. reported that oltipraz, a synthetic Nrf2 activator, increased miR-125b in the kidney of mice [94]. miR-125b subsequently inhibited the activity of aryl hydrocarbon receptor repressor, leading to augmentation of Mdm2 and reduction of p53, thus to protect the kidney against acute injury caused by cisplatin. Table 2 gives a summary of microRNAs associated with Nrf2 signal.

Table 2 Lists of micRNAs associated with Nrf2 signal
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Typical activators and antagonists of Nrf2 signal

Activators of Nrf2 signal have long been studied for their effects in inducing detoxication and cytoprotective genes, generating a chemopreventive effect towards carcinogenesis. Among thousands of newly synthetic or extracted compounds, typical activators of Nrf2 commonly derive from plants such as broccoli [95] and turmeric [96].

Sulforaphane, which is extracted from broccoli, is one of the most potent activators of Nrf2 signal. Hong et al. demonstrated that sulforaphane modified Kelch domain of Keap1 protein [97]. Thiols from Kelch domain react with isothiocyanate on sulforaphane to form a thionoacyl adduct, releasing Nrf2 protein and inducing phase II metabolic enzymes. Kalpana et al. tested the ability of sulforaphane in inhibiting benzo(a)pyrene (B(a)P)-initiated lung carcinogenesis in mouse and confirmed its impact on Nrf2 signal pathway [98]. Intriguingly, sulforaphane could induce apoptosis through ROS-mediated mitochondrial pathway [99].

Curcumin, which is extracted from an Indian spice named turmeric, is also a classical Nrf2 signal activator. A series of studies emphasized its radiation-protective or chemoprevention role in normal tissues and indicated the protective effects are mediated by activating Nrf2 signal [96, 100]. Intriguingly, curcumin yet can act as a radiotherapy/chemotherapy sensitizer in colorectal cancer [101, 102], prostate cancer [103], and ovarian cancer [104]. It is remarkable that curcumin also has an inhibitory effect on other oncogenic signal pathways such as NF-kappa B [104], Notch1 [105], and mitochondrial pathway [106], therefore providing more rationale for its clinical practice in the future.

Oltipraz, known as a dithiolthione substitute capable of inducing phase II enzymes, exhibited a chemoprevention effect [107]. Lida et al. demonstrated that Nrf2 was responsible for oltipraz’s chemoprevention effect against bladder carcinogenesis [108]. Sharma et al. proved that inhalation of oltipraz as spray inhibited B(a)P-initiated lung adenocarcinoma in mouse [109].

CDDO-Im is another powerful activator of Nrf2 signal. It is a synthetic oleanolic triterpenoids that can covalently conjugate with electron-withdrawing groups. Cleasby et al. identified CDDO-Im covalently formed complex with Keap1 on BTB domain [110]. This complex inhibited the binding of Keap1 BTB domain and Cullin3 to activate Nrf2 signal. By applying microarray to Keap1-knockout and CDDO-Im disposed mice, Yates et al. demonstrated that both methods exerted a comprehensive activation of Nrf2-regulated gene [111]. In vivo evidence suggested an oral dose of 1~100 μM/kg CDDO-Im protected hepatic cells against aflatoxin-induced tumorigenesis [112].

As to antagonists of Nrf2 signal, limited compounds were identified to exhibit obvious inhibitory effect. Brusatol is a quassinoid firstly reported to have an antitumor effect for leukemia [113]. Ren et al. found that brusatol enhanced ubiquitination and degradation of Nrf2 and reduced its protein level [114]. Pretreatment with brusatol increased cancer cells’ sensitivity to chemotherapy. In mouse xenograft model, brusatol combined with cisplatin significantly reduced expressions of Nrf2, Nqo1, and Ki-67 indexes. Research also suggested that the inhibitory effect caused by brusatol was a transient process which happened within 12 h after its administration [115]. Posttranscriptional regulation was recognized as the main inhibition mechanism.

Prognostic value of Nrf2 signal in NSCLC

As introduced above, Nrf2 and its downstream transcripts protect cells against exogenous stimuli and oxidant stress, thus increasing lung cancer cells’ resistant to antineoplastic treatment. Inoue et al. examined the expression of Nrf2 by immunohistochemical in 109 NSCLC specimens and discovered that higher nuclear accumulation of Nrf2 correlated with worse lung cancer-specific survival [116]. Solis et al. further explored nuclear Nrf2 and cytoplasm Keap1 immunohistochemical expression in 304 NSCLC patients and reported that nuclear Nrf2 expression associated with worse progress-free survival in squamous cell cancer patients who underwent adjuvant treatment [35]. Yang et al. analyzed Nrf2 abundance of 60 NSCLC patients and compared platinum-based treatments response between patients with <75 % positive stain and that with 75–100 % positive stain [18]. It was discovered that the former group achieved a higher response rate than the latter group, suggesting that Nrf2 expression might be a useful index to predict the efficacy of platinum-based treatments.

As the main negative regulator of Nrf2, Keap1 activity also correlated with NSCLC survival. Muscarella et al. discovered that NSCLC patients harboring both Keap1 somatic mutation and methylation had worse progress-free survival compared with other patients [33]. Similarly, Takahashi et al. found that Keap1 mutations conferred to the increase of Nrf2 abundance in NSCLC patients and worse progress-free and overall survival [117].

With regard to Ho-1, one of Nrf2 downstream transcripts, correlation between its expression and survival has not yet been elucidated. Degese et al. pointed out that Ho-1 expression correlated with advanced stage and lymphatic metastasis, but no associations with patients’ overall survival were found [118]. In study of Tsai et al., Ho-1 expression in 70 NSCLC tumor tissues were assessed with matched normal tissues [119]. The results indicated that patients with a Ho-1 mRNA rise (defined as ratio between tumor and normal bigger than 1) exhibited worse overall survival and higher metastasis rate.

Another important transcript of Nrf2 signal, Nqo1, encoding a flavoprotein previously named DT-diaphorase and mainly acting as a catalyzer of oxidation of NA(D)PH, predicted NSCLC survival at different levels. Early before, Pamela et al. related DT-diaphorase expression and activity in NSCLC tumors to smoking status [120]. Then, Kolesar et al. validated that expressions of Nqo1 in lung tumors were higher than the matched normal lung tissues [121]. Moreover, they also evaluated Nqo1 single nucleotide polymorphism (SNP) by restriction fragment length polymorphism (RFLP), and found that homozygous SNP genotype was associated with worse overall survival [122]. Recently, Li et al. also demonstrated that patients with positive expression of Nqo1 stain in tumors have shorter overall survival [123].

Conclusions

Although Nrf2 has been newly identified as oncogenic signal pathway, it has not been proved to be a driver gene in NSCLC. Nrf2 signal is inextricably linked to classical oncogenic pathways (Fig. 2). MicroRNA played an important role in regulation of Nrf2 signal. Both activators and antagonists towards Nrf2 have been applied in preclinical researches, reflecting its two-side effect during lung tumor initiation and progression. Yet, the effect requires more evidences before putting into clinical practice. Nrf2 signal is characterized as a potential biomarker in NSCLC progress and prognosis.

Fig. 2
figure 2

Schematic illustration of pathways associated with Nrf2 signal. Keap1 assembles Cullin 3 and binds to the ETGE and DLG sites of Nrf2 through Kelch domain, leading to the degradation of Nrf2. In the absence of Keap1, Nrf2 translocates from cytoplasm to nuclear to bind with ARE in the promoter region of target gene, leading to the transcriptional activation of genes related to inflammation, detoxication, and metabolic regulation. However, Nrf2 activity could be modified by acetylation and deacetylation through NF-kappa B or ER pathway. Nrf2 activity could also be inhibited by Bach1 through competitively binding with ARE. Mutant K-ras promotes Nrf2 transcriptional through TPA responsive element. Several microRNAs have been shown to inhibit Nrf2 or Keap1. BTB Broad complex, Tramtrack, and Bric à brac, ARE antioxidant responsive element, ER estrogen receptor, Ub ubiquitin, CBP CREB-binding protein

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Abbreviations

ARE:

antioxidant response element

B(a)P:

benzo(a)pyrene

BTB:

Broad complex, Tramtrack, and Bric à brac

CBP:

CREB-binding protein

EGFR:

epidermal growth factor receptor

EML4-ALK:

echinoderm microtubule-associated protein-like anaplastic lymphoma kinase

ER:

estrogen receptor

Gclm:

glutamate-cysteine ligase modifier subunit

Gst:

glutathione S-transferase

Ho-1:

heme oxygenase-1

Keap1:

Kelch-like ECH-associated protein 1

K-ras:

Kirsten retrovirus-associated DNA sequences

MRP1:

multidrug resistance-associated protein 1

NICD:

Notch intracellular domain

Nqo1:

NAD(P)H quinone oxidoreductase 1

Nrf2:

nuclear factor erythroid 2-like factor 2

NSCLC:

non-small cell lung cancer

PI3K:

phosphatidylinositol 3-kinase

RFLP:

restriction fragment length polymorphism

ROS:

reactive oxygen species

SNP:

single nucleotide polymorphism

t-BHQ:

tertiary butylhydroquinone

TCGA:

The Cancer Genome Atlas

TPM:

total particular matter

TRE:

TPA response element

UTR:

untranslated region

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.

    Article  PubMed  Google Scholar 

  2. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385(9972):977–1010.

    Article  PubMed  Google Scholar 

  3. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.

    Article  CAS  PubMed  Google Scholar 

  4. Sun W, Yuan X, Tian Y, Wu H, Xu H, Hu G, et al. Non-invasive approaches to monitor EGFR-TKI treatment in non-small-cell lung cancer. J Hematol Oncol. 2015;8:95.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 2012;13(10):1011–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, et al. Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015;8(1):17.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Loewen G, Jayawickramarajah J, Zhuo Y, Shan B. Functions of lncRNA HOTAIR in lung cancer. J Hematol Oncol. 2014;7:90.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Dong S, Qu X, Li W, Zhong X, Li P, Yang S, et al. The long non-coding RNA, GAS5, enhances gefitinib-induced cell death in innate EGFR tyrosine kinase inhibitor-resistant lung adenocarcinoma cells with wide-type EGFR via downregulation of the IGF-1R expression. J Hematol Oncol. 2015;8:43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Nguyen D, Rubinstein L, Takebe N, Miele L, Tomaszewski JE, Ivy P, et al. Notch1 phenotype and clinical stage progression in non-small cell lung cancer. J Hematol Oncol. 2015;8:9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Fu QF, Liu Y, Fan Y, Hua SN, Qu HY, Dong SW, et al. Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway. J Hematol Oncol. 2015;8:22.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Suwei D, Liang Z, Zhimin L, Ruilei L, Yingying Z, Zhen L, et al. NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin. J Hematol Oncol. 2015;8(1):120.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Zhong W, Yang X, Yan H, Zhang X, Su J, Chen Z, et al. Phase II study of biomarker-guided neoadjuvant treatment strategy for IIIA-N2 non-small cell lung cancer based on epidermal growth factor receptor mutation status. J Hematol Oncol. 2015;8:54.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Hirsch FR. Squamous cell lung cancer: where do we stand and where are we going? Oncology (Williston Park). 2013;27(9):914–5.

    Google Scholar 

  14. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519–25.

    Article  CAS  Google Scholar 

  15. Kim Y, Hammerman PS, Kim J, Yoon JA, Lee Y, Sun JM, et al. Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients. J Clin Oncol. 2014;32(2):121–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.

    Article  CAS  PubMed  Google Scholar 

  17. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res. 2013;73(13):4158–68.

    Article  CAS  PubMed  Google Scholar 

  18. Yang H, Wang W, Zhang Y, Zhao J, Lin E, Gao J, et al. The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer. Clin Lung Cancer. 2011;12(3):166–71.

    Article  PubMed  Google Scholar 

  19. Canning P, Sorrell FJ, Bullock AN. Structural basis of KEAP1 interactions with Nrf2. Free Radic Biol Med. 2015.

  20. Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, et al. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 2008;68(19):7975–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22(1):66–79.

    Article  CAS  PubMed  Google Scholar 

  22. Aleksunes LM, Goedken MJ, Rockwell CE, Thomale J, Manautou JE, Klaassen CD. Transcriptional regulation of renal cytoprotective genes by Nrf2 and its potential use as a therapeutic target to mitigate cisplatin-induced nephrotoxicity. J Pharmacol Exp Ther. 2010;335(1):2–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015;47(12):1475–81.

    Article  CAS  PubMed  Google Scholar 

  24. Abazeed ME, Adams DJ, Hurov KE, Tamayo P, Creighton CJ, Sonkin D, et al. Integrative radiogenomic profiling of squamous cell lung cancer. Cancer Res. 2013;73(20):6289–98.

    Article  CAS  PubMed  Google Scholar 

  25. Tao S, Wang S, Moghaddam SJ, Ooi A, Chapman E, Wong PK, et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 2014;74(24):7430–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wakabayashi N, Chartoumpekis DV, Kensler TW. Crosstalk between Nrf2 and Notch signaling. Free Radic Biol Med. 2015.

  27. Bryant A, Cerfolio RJ. Differences in epidemiology, histology, and survival between cigarette smokers and never-smokers who develop non-small cell lung cancer. Chest. 2007;132(1):185–92.

    Article  PubMed  Google Scholar 

  28. Landi MT, Dracheva T, Rotunno M, Figueroa JD, Liu H, Dasgupta A, et al. Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS One. 2008;3(2), e1651.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Sekine T, Sakaguchi C, Fukano Y. Investigation by microarray analysis of effects of cigarette design characteristics on gene expression in human lung mucoepidermoid cancer cells NCI-H292 exposed to cigarette smoke. Exp Toxicol Pathol. 2015;67(2):143–51.

    Article  CAS  PubMed  Google Scholar 

  30. Hu Y, Ju Y, Lin D, Wang Z, Huang Y, Zhang S, et al. Mutation of the Nrf2 gene in non-small cell lung cancer. Mol Biol Rep. 2012;39(4):4743–7.

    Article  CAS  PubMed  Google Scholar 

  31. Sasaki H, Suzuki A, Shitara M, Hikosaka Y, Okuda K, Moriyama S, et al. Genotype analysis of the NRF2 gene mutation in lung cancer. Int J Mol Med. 2013;31(5):1135–8.

    CAS  PubMed  Google Scholar 

  32. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10), e420.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Muscarella LA, Parrella P, D’Alessandro V, la Torre A, Barbano R, Fontana A, et al. Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics. 2011;6(6):710–9.

    Article  CAS  PubMed  Google Scholar 

  34. Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, et al. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 2010;16(14):3743–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Cescon DW, She D, Sakashita S, Zhu CQ, Pintilie M, Shepherd FA, et al. NRF2 pathway activation and adjuvant chemotherapy benefit in lung squamous cell carcinoma. Clin Cancer Res. 2015;21(11):2499–505.

    Article  CAS  PubMed  Google Scholar 

  37. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, et al. The Cap’n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res. 2001;61(8):3299–307.

    CAS  PubMed  Google Scholar 

  39. Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A. 2004;101(7):2046–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci U S A. 2001;98(6):3404–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Theodore M, Kawai Y, Yang J, Kleshchenko Y, Reddy SP, Villalta F, et al. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2. J Biol Chem. 2008;283(14):8984–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Jain AK, Bloom DA, Jaiswal AK. Nuclear import and export signals in control of Nrf2. J Biol Chem. 2005;280(32):29158–68.

    Article  CAS  PubMed  Google Scholar 

  43. Venugopal R, Jaiswal AK. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A. 1996;93(25):14960–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Alam J, Stewart D, Touchard C, Boinapally S, Choi AM, Cook JL. Nrf2, a Cap’n’Collar transcription factor, regulates induction of the heme oxygenase-1 gene. J Biol Chem. 1999;274(37):26071–8.

    Article  CAS  PubMed  Google Scholar 

  45. Wang XJ, Hayes JD, Wolf CR. Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of nrf2 by cancer chemotherapeutic agents. Cancer Res. 2006;66(22):10983–94.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol. 2003;23(22):8137–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A. 2002;99(18):11908–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Wang XJ, Li Y, Luo L, Wang H, Chi Z, Xin A, et al. Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs. Free Radic Biol Med. 2014.

  49. McMahon M, Lamont DJ, Beattie KA, Hayes JD. Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc Natl Acad Sci U S A. 2010;107(44):18838–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells. 2001;6(10):857–68.

    Article  CAS  PubMed  Google Scholar 

  51. Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med. 2004;36(10):1199–207.

    Article  CAS  PubMed  Google Scholar 

  52. Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013;27(20):2179–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Rosvold EA, McGlynn KA, Lustbader ED, Buetow KH. Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. Pharmacogenetics. 1995;5(4):199–206.

    Article  CAS  PubMed  Google Scholar 

  54. Elguero B, Gueron G, Giudice J, Toscani MA, De Luca P, Zalazar F, et al. Unveiling the association of STAT3 and HO-1 in prostate cancer: role beyond heme degradation. Neoplasia. 2012;14(11):1043–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Dey S, Sayers CM, Verginadis II, Lehman SL, Cheng Y, Cerniglia GJ, et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Invest. 2015.

  56. Tertil M, Golda S, Skrzypek K, Florczyk U, Weglarczyk K, Kotlinowski J, et al. Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: antitumoral effects associated with down-regulation of matrix metalloproteinases. Free Radic Biol Med. 2015;89:147–57.

    Article  CAS  PubMed  Google Scholar 

  57. Tertil M, Skrzypek K, Florczyk U, Weglarczyk K, Was H, Collet G, et al. Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer: crosstalk with Nrf2 and HO-1. PLoS One. 2014;9(5), e97070.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Ji L, Li H, Gao P, Shang G, Zhang DD, Zhang N, et al. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One. 2013;8(5), e63404.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Dinkova-Kostova AT, Baird L, Holmstrom KM, Meyer CJ, Abramov AY. The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics. Biochem Soc Trans. 2015;43(4):602–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Dinkova-Kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;88(Pt B):179–88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Kovac S, Angelova PR, Holmstrom KM, Zhang Y, Dinkova-Kostova AT, Abramov AY. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta. 2015;1850(4):794–801.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Agyeman AS, Chaerkady R, Shaw PG, Davidson NE, Visvanathan K, Pandey A, et al. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res Treat. 2011;132(1):175–87.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Greco T, Shafer J, Fiskum G. Sulforaphane inhibits mitochondrial permeability transition and oxidative stress. Free Radic Biol Med. 2011;51(12):2164–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res. 2008;103(11):1232–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.

    Article  CAS  PubMed  Google Scholar 

  66. Califano R, Landi L, Cappuzzo F. Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. Drugs. 2012;72 Suppl 1:28–36.

    Article  CAS  PubMed  Google Scholar 

  67. Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323(9):561–5.

    Article  CAS  PubMed  Google Scholar 

  68. Marks JL, Broderick S, Zhou Q, Chitale D, Li AR, Zakowski MF, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 2008;3(2):111–6.

    Article  PubMed  Google Scholar 

  69. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475(7354):106–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK. Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem. 2005;280(17):16891–900.

    Article  CAS  PubMed  Google Scholar 

  71. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002;21(19):5216–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Reichard JF, Motz GT, Puga A. Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1. Nucleic Acids Res. 2007;35(21):7074–86.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, et al. In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Endocrinology. 2004;145(1):311–7.

    Article  CAS  PubMed  Google Scholar 

  74. Yao Y, Brodie AM, Davidson NE, Kensler TW, Zhou Q. Inhibition of estrogen signaling activates the NRF2 pathway in breast cancer. Breast Cancer Res Treat. 2010;124(2):585–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325(5942):834–40.

    Article  CAS  PubMed  Google Scholar 

  76. Santos L, Escande C, Denicola A. Potential modulation of sirtuins by oxidative stress. Oxid Med Cell Longev. 2016; doi: 10.1155/2016/9831825.

  77. Kawai Y, Garduno L, Theodore M, Yang J, Arinze IJ. Acetylation-deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem. 2011;286(9):7629–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Buelna-Chontal M, Zazueta C. Redox activation of Nrf2 & NF-kappaB: a double end sword? Cell Signal. 2013;25(12):2548–57.

    Article  CAS  PubMed  Google Scholar 

  79. Liu GH, Qu J, Shen X. NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta. 2008;1783(5):713–27.

    Article  CAS  PubMed  Google Scholar 

  80. Rushworth SA, Zaitseva L, Murray MY, Shah NM, Bowles KM, MacEwan DJ. The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance. Blood. 2012;120(26):5188–98.

    Article  CAS  PubMed  Google Scholar 

  81. Snell CE, Turley H, McIntyre A, Li D, Masiero M, Schofield CJ, et al. Proline-hydroxylated hypoxia-inducible factor 1alpha (HIF-1alpha) upregulation in human tumours. PLoS One. 2014;9(2), e88955.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  82. Loboda A, Stachurska A, Florczyk U, Rudnicka D, Jazwa A, Wegrzyn J, et al. HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells. Antioxid Redox Signal. 2009;11(7):1501–17.

    Article  CAS  PubMed  Google Scholar 

  83. Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, et al. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res. 2011;71(6):2260–75.

    Article  CAS  PubMed  Google Scholar 

  84. Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7(1):87.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 2015.

  86. Yuan X, Wu H, Xu H, Han N, Chu Q, Yu S, et al. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep. 2015;5:10338.

    Article  PubMed Central  PubMed  Google Scholar 

  87. Wakabayashi N, Skoko JJ, Chartoumpekis DV, Kimura S, Slocum SL, Noda K, et al. Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol Cell Biol. 2014;34(4):653–63.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  88. Paul MK, Bisht B, Darmawan DO, Chiou R, Ha VL, Wallace WD, et al. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. Cell Stem Cell. 2014;15(2):199–214.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Zhao Q, Mao A, Yan J, Sun C, Di C, Zhou X, et al. Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells. Int J Oncol. 2016;48(2):765–73.

    PubMed  Google Scholar 

  90. Yang M, Yao Y, Eades G, Zhang Y, Zhou Q. MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat. 2011;129(3):983–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Yamamoto S, Inoue J, Kawano T, Kozaki K, Omura K, Inazawa J. The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors. Mol Cancer Res. 2014;12(1):58–68.

    Article  CAS  PubMed  Google Scholar 

  92. Eades G, Yang M, Yao Y, Zhang Y, Zhou Q. miR-200a regulates Nrf2 activation by targeting Keap1 mRNA in breast cancer cells. J Biol Chem. 2011;286(47):40725–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest. 2013;123(7):2921–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Joo MS, Lee CG, Koo JH, Kim SG. miR-125b transcriptionally increased by Nrf2 inhibits AhR repressor, which protects kidney from cisplatin-induced injury. Cell Death Dis. 2013;4:e899.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Shishu, Kaur IP. Inhibition of mutagenicity of food-derived heterocyclic amines by sulforaphane—a constituent of broccoli. Indian J Exp Biol. 2003;41(3):216–9.

    CAS  PubMed  Google Scholar 

  96. Goel A, Aggarwal BB. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 2010;62(7):919–30.

    Article  CAS  PubMed  Google Scholar 

  97. Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005;18(12):1917–26.

    Article  CAS  PubMed  Google Scholar 

  98. Kalpana Deepa Priya D, Gayathri R, Sakthisekaran D. Role of sulforaphane in the anti-initiating mechanism of lung carcinogenesis in vivo by modulating the metabolic activation and detoxification of benzo(a)pyrene. Biomed Pharmacother. 2011;65(1):9–16.

    Article  CAS  PubMed  Google Scholar 

  99. Jo GH, Kim GY, Kim WJ, Park KY, Choi YH. Sulforaphane induces apoptosis in T24 human urinary bladder cancer cells through a reactive oxygen species-mediated mitochondrial pathway: the involvement of endoplasmic reticulum stress and the Nrf2 signaling pathway. Int J Oncol. 2014;45(4):1497–506.

    CAS  PubMed  Google Scholar 

  100. Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis. 2008;29(5):1022–32.

    Article  CAS  PubMed  Google Scholar 

  101. Li L, Ahmed B, Mehta K, Kurzrock R. Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer. Mol Cancer Ther. 2007;6(4):1276–82.

    Article  CAS  PubMed  Google Scholar 

  102. Kunnumakkara AB, Diagaradjane P, Guha S, Deorukhkar A, Shentu S, Aggarwal BB, et al. Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products. Clin Cancer Res. 2008;14(7):2128–36.

    Article  CAS  PubMed  Google Scholar 

  103. Li M, Zhang Z, Hill DL, Wang H, Zhang R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer Res. 2007;67(5):1988–96.

    Article  CAS  PubMed  Google Scholar 

  104. Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN, et al. Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res. 2007;13(11):3423–30.

    Article  CAS  PubMed  Google Scholar 

  105. Li Y, Zhang J, Ma D, Zhang L, Si M, Yin H, et al. Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling. FEBS J. 2012;279(12):2247–59.

    Article  CAS  PubMed  Google Scholar 

  106. Wu SH, Hang LW, Yang JS, Chen HY, Lin HY, Chiang JH, et al. Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. Anticancer Res. 2010;30(6):2125–33.

    CAS  PubMed  Google Scholar 

  107. Choi SH, Kim YM, Lee JM, Kim SG. Antioxidant and mitochondrial protective effects of oxidized metabolites of oltipraz. Expert Opin Drug Metab Toxicol. 2010;6(2):213–24.

    Article  CAS  PubMed  Google Scholar 

  108. Iida K, Itoh K, Kumagai Y, Oyasu R, Hattori K, Kawai K, et al. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res. 2004;64(18):6424–31.

    Article  CAS  PubMed  Google Scholar 

  109. Sharma S, Gao P, Steele VE. The chemopreventive efficacy of inhaled oltipraz particulates in the B[a]P-induced A/J mouse lung adenoma model. Carcinogenesis. 2006;27(8):1721–7.

    Article  CAS  PubMed  Google Scholar 

  110. Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One. 2014;9(6), e98896.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  111. Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis. 2009;30(6):1024–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Yates MS, Kwak MK, Egner PA, Groopman JD, Bodreddigari S, Sutter TR, et al. Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 2006;66(4):2488–94.

    Article  CAS  PubMed  Google Scholar 

  113. Hall IH, Lee KH, Eigebaly SA, Imakura Y, Sumida Y, Wu RY. Antitumor agents. XXXIV: mechanism of action of bruceoside A and brusatol on nucleic acid metabolism of P-388 lymphocytic leukemia cells. J Pharm Sci. 1979;68(7):883–7.

    Article  CAS  PubMed  Google Scholar 

  114. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A. 2011;108(4):1433–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, et al. Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med. 2015;78:202–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Inoue D, Suzuki T, Mitsuishi Y, Miki Y, Suzuki S, Sugawara S, et al. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci. 2012;103(4):760–6.

    Article  CAS  PubMed  Google Scholar 

  117. Takahashi T, Sonobe M, Menju T, Nakayama E, Mino N, Iwakiri S, et al. Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. J Surg Oncol. 2010;101(6):500–6.

    CAS  PubMed  Google Scholar 

  118. Degese MS, Mendizabal JE, Gandini NA, Gutkind JS, Molinolo A, Hewitt SM, et al. Expression of heme oxygenase-1 in non-small cell lung cancer (NSCLC) and its correlation with clinical data. Lung Cancer. 2012;77(1):168–75.

    Article  PubMed  Google Scholar 

  119. Tsai JR, Wang HM, Liu PL, Chen YH, Yang MC, Chou SH, et al. High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients. Cell Oncol (Dordr). 2012;35(6):461–71.

    Article  CAS  Google Scholar 

  120. Gasdaska PY, Powis G, Hyman P, Fisher H. Cigarette smoking is a determinant of DT-diaphorase gene expression in human non-small cell lung carcinoma. Cancer Res. 1993;53(22):5458–61.

    CAS  PubMed  Google Scholar 

  121. Kolesar JM, Pritchard SC, Kerr KM, Kim K, Nicolson MC, McLeod H. Evaluation of NQO1 gene expression and variant allele in human NSCLC tumors and matched normal lung tissue. Int J Oncol. 2002;21(5):1119–24.

    CAS  PubMed  Google Scholar 

  122. Kolesar JM, Dahlberg SE, Marsh S, McLeod HL, Johnson DH, Keller SM, et al. The NQO1*2/*2 polymorphism is associated with poor overall survival in patients following resection of stages II and IIIa non-small cell lung cancer. Oncol Rep. 2011;25(6):1765–72.

    PubMed Central  PubMed  Google Scholar 

  123. Li Z, Zhang Y, Jin T, Men J, Lin Z, Qi P, et al. NQO1 protein expression predicts poor prognosis of non-small cell lung cancers. BMC Cancer. 2015;15:207.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 81572608, 81301929) and Wuhan Yellow Crane Medical Talent Program Grant No.2015-12.

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  1. Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Building 303, 1095 Jiefang Avenue, Wuhan, 430030, People’s Republic of China

    Yijun Tian, Qian Liu, Xun Yuan, Yuan Chen, Qian Chu & Kongming Wu

  2. Clinical Research Center, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, 430030, People’s Republic of China

    Xuelian He

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  1. Yijun Tian
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Authors’ contributions

YT and QL searched the literatures and performed the analysis. XH and XY prepared the tables and figures. QC and YC discussed and revised the manuscript. KW designed the study and drafted the manuscript. All authors had edit and approved the final manuscript.

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Tian, Y., Liu, Q., He, X. et al. Emerging roles of Nrf2 signal in non-small cell lung cancer. J Hematol Oncol 9, 14 (2016). https://0-doi-org.brum.beds.ac.uk/10.1186/s13045-016-0246-5

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  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s13045-016-0246-5

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Journal of Hematology & Oncology

ISSN: 1756-8722

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