Thirty-four years since its discovery, NF-κB remains a transcription factor with great potential for cancer therapy. However, NF-κB–targeted therapies have yet to find a way to be clinically translatable. Here, we focus exclusively on the role of NF-κB in non-small cell lung cancer (NSCLC) and discuss its contributing effect on cancer hallmarks such as inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial–mesenchymal transition, metastasis, stemness, metabolism, and therapy resistance. In addition, we present our current knowledge of the clinical significance of NF-κB and its involvement in the treatment of patients with NSCLC with chemotherapy, targeted therapies, and immunotherapy.

In 1986, NF-κB, a new transcription factor that binds to the enhancer of κ immunoglobulins in activated B cells, was isolated for the first time and characterized by Sen and Baltimore (1). Due to its induction during B-cell maturation, it was initially thought to exert a significant role in B-cell activation and development (2). Since then, research on NF-κB has been progressively expanding, proving that its role is not limited only to B cells but it is involved in many biological processes (3). The potential of NF-κB to modify many biological aspects of cells is linked to the expression profiles of hundreds of target genes, whose transcription is regulated by its transactivating or transrepressive activity (4). NF-κB has been ubiquitously detected and regulates essential functions in the vast majority of cell types, such as proliferation, development, survival, and cell death (5, 6). In addition, NF-κB is also responsible for the transcription of genes with antiapoptotic properties (7, 8), genes implicated in self-regulation (9, 10), genes coding growth factors, angiogenesis-related genes, and cell adhesion molecules (4, 11). Furthermore, NF-κB is implicated in the regulation of genes that participate in immunosurveillance (4), in functions of the immune system (12), and in inflammation (13). A wide variety of agents including stress signals, infectious agents, free radicals, carcinogens, and endotoxins can induce the activation of NF-κB (14). Moreover, NF-κB plays a pivotal role in cigarette smoke-induced carcinogenesis (15, 16). Due to its key role in every aspect of a cell's life and its aberrant regulation in pathologic conditions, the NF-κB pathway has become an attractive therapeutic target for many diseases including non–small cell lung cancer (NSCLC; refs. 17, 18).

NF-κB represents a family of important transcription factors (Rel proteins), which have structural similarities. This family consists of five members [NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-Rel], which generate five transcriptionally active molecules (Fig. 1). NF-κB1 and NF-κB2 are initially transcribed as longer precursors, p105 and p100, respectively, which, through posttranslational modifications, result in the functional subunits p50 and p52, respectively (19). The transcriptional significance of NF-κB is based on its ability to form biologically active complexes that are either homodimers or heterodimers (4). A well-conserved region at the N-terminus, REL homology domain, which is common in NF-κB/Rel proteins, embraces dimerization and DNA-binding functions (19, 20). RelA, RelB, and c-Rel each contain a transcriptional activation domain at the carboxyl end enabling dimers to act as transcriptional activators (5, 19).

Figure 1.

Structural traits of NF-κB family members. Rel homology domain (RHD) is a highly conserved amino-terminal domain shared among NF-κB transcription factors that mediates dimerization, nuclear translocation, DNA binding, and interaction with inhibitory IκB proteins. Transcriptional activation domain (TAD) is another carboxy-terminal pivotal domain of RelA, RelB, and c-Rel. p100 and p105 share an ankyrin-containing domain (a), which plays an important role in subcellular compartmentalization of the aforementioned molecules. a, ankyrin repeats; DD, death domain; GR, glycine-rich region; LZ, leucine zipper.

Figure 1.

Structural traits of NF-κB family members. Rel homology domain (RHD) is a highly conserved amino-terminal domain shared among NF-κB transcription factors that mediates dimerization, nuclear translocation, DNA binding, and interaction with inhibitory IκB proteins. Transcriptional activation domain (TAD) is another carboxy-terminal pivotal domain of RelA, RelB, and c-Rel. p100 and p105 share an ankyrin-containing domain (a), which plays an important role in subcellular compartmentalization of the aforementioned molecules. a, ankyrin repeats; DD, death domain; GR, glycine-rich region; LZ, leucine zipper.

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The five members of the NF-κB family can be combined into 15 possible dimers, although only 12 of them have been characterized (21). The most investigated complexes of NF-κB are the heterodimers p50/p65 and p52/RelB (Fig. 2). The first heterodimer is the final effector complex of the classical or canonical pathway, whereas the alternative or noncanonical pathway mainly includes the p52/RelB heterodimer (Fig. 2; ref. 22). Although classical and alternative pathways of NF-κB have attracted the interest of the scientific community, hybrid signaling pathways have also been reported, within the cross-interaction of the two pathways and different heterodimers (e.g., p52/p65 or p52/c-Rel) that have previously been described (23).

Figure 2.

The two major NF-κB pathways (classical and alternative). The activation of the classical pathway (left-hand side) mainly leads to the formation of an active heterodimer of p50:RelA, which modifies multiple gene expression by binding to κB-binding sites. The alternative pathway (right-hand side) regulates gene expression through the binding of the central complex p52:RelB. Many other heterodimers and homodimers of p50 and p52 are formed by increasing further the complexity of the NF-κB system. Abbreviations: TCR, T-cell receptor; NEMO, NF-kappa-B essential modulator; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor; BAFFR, tumor necrosis factor receptor superfamily member 13C; CD40, CD40 molecule, TNF receptor superfamily member 5; LTβR, lymphotoxin beta receptor (TNFR Superfamily, Member 3); RANK, receptor activator of nuclear factor-kappa B; p100, nuclear factor NF-kappa-B p100 subunit; p52, nuclear factor NF-kappa-B p52 subunit; RelB, transcription factor RelB.

Figure 2.

The two major NF-κB pathways (classical and alternative). The activation of the classical pathway (left-hand side) mainly leads to the formation of an active heterodimer of p50:RelA, which modifies multiple gene expression by binding to κB-binding sites. The alternative pathway (right-hand side) regulates gene expression through the binding of the central complex p52:RelB. Many other heterodimers and homodimers of p50 and p52 are formed by increasing further the complexity of the NF-κB system. Abbreviations: TCR, T-cell receptor; NEMO, NF-kappa-B essential modulator; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor; BAFFR, tumor necrosis factor receptor superfamily member 13C; CD40, CD40 molecule, TNF receptor superfamily member 5; LTβR, lymphotoxin beta receptor (TNFR Superfamily, Member 3); RANK, receptor activator of nuclear factor-kappa B; p100, nuclear factor NF-kappa-B p100 subunit; p52, nuclear factor NF-kappa-B p52 subunit; RelB, transcription factor RelB.

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The classical pathway is characterized by a fast and transient activation and response, a priority that ensures the transcription of genes for a primary immunological response (13). Receptors of TNF (TNFR), IL1R, and toll-like receptors bind with ligands such as lipopolysaccharide and bacterial DNA, as well as antigen receptors, to activate the classical pathway through phosphorylation of IκB kinase β (IKKβ; Fig. 2; ref. 24). Thereafter, IKKβ phosphorylates IκB, which, prior to phosphorylation, forms a complex with heterodimer p50/p65. Its phosphorylation leads to the release of p50/p65, which is then translocated to the nucleus, where it exerts its transcriptional activity by binding to κB sites (22).

The alternative NF-κB pathway can be activated by members of TNF superfamily, such as lymphotoxin β (LTβ), tumor necrosis factor ligand superfamily member 5 (CD40L), B-cell activation factor (BAFF), receptor activator of NF-κB ligand (RANKL), or the TNF-like weak inducer of apoptosis, as well as viruses such as Epstein–Barr virus and human T-lymphotropic virus type 1 (23). Intracellularly, NF-kappa-B–inducing kinase (NIK) plays a pivotal role in the transduction and the regulation of cell signaling. NIK, which is also known as mitogen-activated protein kinase kinase kinase 14 (MAP3K14), belongs to the family of mitogen-associated proteins and is essential for the activation of p100 (NF-κB2; ref. 25). In particular, NIK activation leads to the activation of IκB kinase α (IKKα), which mediates the phosphorylation of p100 (Fig. 2; ref. 26). Phosphorylation of p100 leads to ubiquitination, which finally propels its degradation by the proteasome, giving rise to p52 (27). Then, p52 is translocated to the nucleus by conforming a homodimer or a heterodimer (e.g., with RelB), where the complex acts as a transcription factor (28).

The alternative NF-κB pathway has been characterized by a delay in response and is dependent on protein synthesis due to NIK constitutive degradation (26). In the absence of stimuli, NIK protein levels are very low as it undergoes ongoing degradation due to its ubiquitination, whereas activation of the pathway induces NIK stabilization and accumulation, which requires a de novo synthesis (29). In addition, this pathway is implicated in thymus organogenesis, self-tolerance, the formation of secondary lymphoid organs, the development of B cells, and osteoclastogenesis. In addition, its role has been studied in cancer initiation and progression (30, 31).

A large number of studies have uncovered the essential contribution of NF-κB to cancer development and progression as well as its potential for cancer treatment (32). It is well documented that NF-κB is activated by a great variety of viruses, bacterial endotoxins, carcinogens, chemotherapeutics, cytokines, and radiation (33), confirming the role of NF-κB in cell integrity and cellular self-defense (34). Due to its multilayer and multidimensional roles, as well as the opposing functions of NF-κB in cancer, its inhibition has been characterized as a “double-edged sword” (35). Although it plays a crucial role and may have pivotal significance for launching an appropriate immune response against cancer, concurrently, it orchestrates inflammation and links chronic inflammation with oncogenesis (36). In addition, activated NF-κB may influence the progression of a tumor either positively or negatively (37). In many cancer types, NF-κB is particularly deregulated, both in tumor cells and in the tumor microenvironment (38), although differences in its expression are not always accompanied by pathway activation. Here, we review exclusively the significance of NF-κB in pathogenesis and in the clinical practice of managing NSCLC.

The remarkable role of NF-κB in lung cancer has mainly been elucidated with studies using genetically engineered mouse models for lung cancer. Xiao and colleagues, after establishing a kinase-dead IKKα knock-in mouse model, found that IKKα downregulation predisposes to pulmonary inflammation and spontaneous development of lung squamous cell carcinoma development (39). Xia and colleagues, after developing a lentiviral vector–mediated mouse model (KrasG12D;IKK2−/−), documented that IKKβ knockout in tumor cells significantly reduced tumor proliferation and prolonged survival in the mice (40). Another significant observation came from K-rasLSL-G12D/WT; p53Flox/Flox mice, where the activation of oncogenic K-rasG12D and concomitant loss of p53 resulted in an increased nuclear translocation of the NF-κB (p65). In addition, inhibition of the NF-κB pathway in vivo by IκB has shown that it can reduce tumor development (41). Moreover, using an inducible transgenic mouse model with specific expression of an NF-κB inhibitor in airway epithelium, Stathopoulos and colleagues documented that urethane-induced lung inflammation, as well as tumor formation, was particularly decreased (42). In addition, preclinical models have demonstrated that the benzopyrene-induced tumor transformation of human bronchial epithelial cells is promoted by macrophages based on NF-κB and STAT3 signaling (43). Furthermore, evidence derived from a urethane-induced model of preclinical lung tumors showed that activation of the epithelial NF-κB pathway leads to chronic airway inflammation, recruitment of an increasing number of functional regulatory T cells (Treg) in an NF-κB–dependent manner, and promotion of lung tumor development (44). Also, Takahashi and colleagues have proved, using knockout mice models, that the induction of inflammation and promotion of lung tumorigenesis by tobacco smoke are mediated by both IKKβ and c-Jun N-terminal kinase 1 in myeloid cells (45). A very interesting observation is that NF-κB is crucial for the rejection of immunogenic tumors in mice, inducing the expression of T-cell chemokines (46). In addition, the same group has shown that NF-κB activity can be reflected by an RNA gene expression signature (both inflammatory and immune response genes; ref. 46). In addition, Deng and colleagues, using mice with a knockout of their tumor suppressor Gprc5a (G-protein–coupled receptor class C group 5 member A), demonstrated that the loss of the Gprc5a augments NF-κB activation in lung epithelial cells, increasing inflammation, which contributes to the formation of a tumor-promoting microenvironment (47).

NF-κB is a key signaling pathway for the respiratory system because RelA has been associated with maturation during lung morphogenesis through alteration of the apoptotic processes of lung epithelial cells (48). It seems that increased RelA in the mesenchyme represses budding in the lungs of developing chicks (49). Furthermore, it has been shown, by inhibition of NF-κB constitutive activation, that NF-κB is a direct regulator of VEGFR2, which plays an essential role in pulmonary angiogenesis and alveolarization during postnatal development (50).

NF-κB is a master regulator, not only of the physiologic and complicated process of lung morphogenesis but also of lung cancer pathogenesis and progression. It is known that NF-κB in NSCLC has a bidirectional contribution because, on one hand, it plays a crucial role in the immune response, whereas on the other hand, it promotes the inflammation that ignites the process of oncogenesis (11). Hence, activated NF-κB signaling may influence the progression of a lung tumor either positively or negatively (37). It is well documented that NF-κB is activated by a great variety of carcinogens, chemotherapeutics, cytokines, and radiation exposure (33). In addition, it has been found that NF-κB participates in and orchestrates many significant functions that tumors require, such as transformation, proliferation, infiltration, angiogenesis, and metastasis. In particular, several studies have demonstrated that NF-κB in NSCLC specifically influences inflammation, proliferation, survival, apoptosis, angiogenesis, epithelial–mesenchymal transition (EMT), metastasis, stemness, metabolism, and therapy resistance (Supplementary Fig. S1; refs. 51, 52).

Inflammation

The role of NF-κB in the initiation and progression of NSCLC is complicated and not yet fully elucidated (51). It is well documented that NF-κB plays a significant role not only in advancing tumor development but also in the preliminary stages of oncogenesis (53). As we mentioned earlier, Zaynagetdinov and colleagues have shown, in a urethane-induced preclinical model of a lung tumor, that activation of the epithelial NF-κB pathway leads to chronic airway inflammation, recruiting increasing functional Tregs in an NF-κB–dependent manner that promotes the development of lung tumors (44). In particular, exposure to smoke and asbestos has been previously associated with DNA damage caused by free radicals and the promotion of chronic inflammation, which is related to the induction of intracellular signaling pathways associated with apoptosis (54). The major transcription factor of inflammation is the NF-κB, as it has under its transcriptional control many interleukins, such as IL6 (55). IL6 may act, either through a paracrine or autocrine way, by activating transcription factor STAT3, and it has been shown that it can promote lung cancer in vivo (56, 57).

Proliferation

Activation of NF-κB in lung epithelial cells has been associated with cellular proliferation through the upregulation of cyclin D1 and the suppression of phosphatase and the tensin homolog (PTEN; ref. 53). Moreover, activation of the NF-κB and subsequent upregulation of cyclin D1 in a normal human bronchial cell by NNK, a tobacco-specific nitrosamine, can stimulate proliferation as well (58). It has also been shown that miR-505, which is downregulated in NSCLC, can inhibit cellular proliferation, migration, invasion, and EMT in NSCLC by targeting the AKT (RAC-alpha serine/threonine-protein kinase)–NF-κB pathway signaling (59). Furthermore, Zhou and colleagues have reported that galectin-3, a ligand of toll-like receptor 4 (TLR4), activates TLR4 signaling, leading to NF-κB (p65) nucleus translocation and promoting lung adenocarcinoma cellular proliferation and migration through the induction of lncRNA-NEAT1 (nuclear enriched abundant transcript 1) expression (60). Another study showed that TRIM13 (tripartite motif-containing 13), whose expression is decreased in NSCLC, can inhibit cell proliferation and apoptosis through modulation of NF-κB signaling (61).

Survival/apoptosis

It is well known that NF-κB promotes tumor survival by modifying apoptosis, transactivating the expression of antiapoptotic genes (8). NF-κB modulates PTEN, which negatively regulates the PI3K/AKT signaling pathway and thus cell survival (62). In addition, NF-κB activation leads to the transcription of the transcription factor Snail, which functions as a transcription suppressor of PTEN (63). BCL2 (apoptosis regulator Bcl-2), which is known for its antiapoptotic role, is another target of NF-κB transcription activity. Overexpression of BCL2 has been associated with smoking and chronic inflammation, impeding of apoptosis, and incorporation of a high number of mutations (53). Jones and colleagues showed, in NSCLC cell line H157, that chemotherapy-related apoptosis can be triggered by inhibiting NF-κB (64). It is also worth mentioning that the tumor microenvironment of NSCLC can induce apoptosis of activated T lymphocytes through the secretion of soluble factors, which, in turn, impair NF-κB signaling in T lymphocytes by an IKK-dependent pathway (65).

Angiogenesis

Angiogenesis is a crucial step in lung cancer tumor initiation, progression, and recurrence (66, 67). Neovasculature affects the effectiveness of lung cancer treatments, such as chemotherapy (68), immune-checkpoint inhibitors, anti-EGFR tyrosine kinase inhibitors (TKI; ref. 69) and chimeric antigen receptor T cells (70). Notably, antiangiogenic targeting alone (71) or in combination with other classes of drugs, such as immune checkpoint inhibitors, have attracted the interest of thoracic oncologists and are under clinical evaluation (72, 73).

NF-κB has a role in cancer angiogenesis as well because it regulates the transcription of proangiogenic factors, such as VEGF and IL8 (74). In cocultivation of IL1β-expressing lung cancer cells with macrophages, the production of VEGFA and IL8, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 was blocked after NF-κB inhibition (75). Moreover, a number of studies have shown that, under hypoxia, NF-κB induces the transcriptional upregulation of hypoxia-inducible factor-1 alpha (HIF1α), which in turn controls genes involved in angiogenesis (76–78). Similarly, Belaiba and colleagues have shown that hypoxic conditions induce NF-κB activation, leading to the expression of HIF1α in the smooth muscle cells of pulmonary arteries (79). Recently, it was also shown that inhibition of IKKβ reduces vascularity in K-RAS–mutant lung cancer xenografts, suggesting a role for IKKβ in fostering KRAS-induced angiogenesis (80).

Metastasis/EMT

The strong association of NF-κB with metastasis has been demonstrated primarily in studies using in vivo models. In particular, inoculation of adenocarcinoma cells in mouse models was associated with a higher number of metastases, particularly when RelA was activated in the epithelial cells of the airways (81). Also, it has been documented that NF-κB can increase the infiltrating potential of malignant lung cells through suppression of the tumor suppressor protein CRMP-1 (collapsin response mediator protein 1), a transmembrane protein, which prevents the infiltration of tumor-adjacent tissues. In the C11-5 lung adenocarcinoma cell line, binding of p50 to κB sites of CRMP-1 promoter suppressed its expression, whereas transfection with antisense p50 increased CRMP-1 and reduced the metastatic potential (82). In addition, IκBβ expression in A549 lung adenocarcinoma cells inhibited metastasis when they were injected into mouse models (83). Moreover, NF-κB increases the transcription of αvβ3 integrin, which participates in the metastasis of lung cancer cells and activates the NF-κB signaling (84). Another study by Fong and colleagues found that osteopontin activates its receptor, αvβ3 integrin in A549 cells, which in turn activates NF-κB, focal adhesion kinase, PI3K, AKT, and ERK pathways, achieving an increase of the migration rates of lung cancer cells (85). Another perspective of the role of NF-κB in metastasis comes from its strong interaction with the tumor microenvironment, which promotes migration. It has been reported that resistin, which is secreted by tumor-associated macrophages (TAM) in tumor tissues, promotes migration of A549 cells through the TLR4/proto-oncogene tyrosine-protein kinase Src (Src)/EGFR/PI3K/NF-κB pathway (86). Moreover, nuclear histone deacetylase 6 (HDAC6) inhibits metastasis by the RelA deacetylation along with a subsequent decrease of matrix metalloproteinase-2 (MMP2) expression, which further supports the role of NF-κB in the NSCLC metastatic process (87). On the other hand, CARD-recruited membrane-associated protein 3, a regulator of NF-κB activation, promotes NSCLC via the negative regulation of nucleoside diphosphate kinase B, a suppressor of metastasis, by NF-κB–dependent induction of miR-182 (88).

NF-κB has also been associated with another significant and highly conserved cellular dedifferentiation program, EMT, which is a prerequisite for metastasis (52). By using in vitro models, Kumar and colleagues showed that NF-κB upregulates the transcription of master-switch transcription factors, which are required for EMT in NSCLC (89). Another study showed that cigarette smoke extract promotes EMT and cellular transformation by activating NF-κB (90). Interestingly, Tian and colleagues have documented that RelA regulates three pathways (the Wnt/β-catenin morphogen pathway, and the pathways of JUN transcription factor and the Snail family transcriptional repressor 1), which exert a crucial role in EMT in epithelial cells in the airway (91). Another study published by Asgarova and colleagues reported that, during EMT, programmed cell death-ligand 1 (PD-L1) expression is regulated by both the NF-κB/IKKϵ pathway and the demethylation of its promoter (92). In addition, chondroitin sulfate proteoglycan serglycin (SRGN), a factor that is secreted from cancer-associated fibroblasts, promotes EMT through CD44/NF-κB/claudin-1 axis (93).

Cancer stemness

Another lung cancer hallmark is cancer stemness, which has been implicated in tumor initiation, metastasis, recurrence, and treatment resistance in various types of cancer (94). Stemness refers not only to cancer stem cells (CSC) of tumors but also to cancer cells with a stem cell phenotype, and it plays an essential role in cancer progression and survival (95).

The association of NF-κB signaling with CSCs and stemness has been reported and confirmed in many cancer types (96, 97). However, detailed knowledge in regards to NSCLC is still quite limited. The involvement of the NF-κB pathway has been described in the regulation of CSCs in NSCLC by Zakaria and colleagues who reported that inhibition of NF-κB using an inhibitor of IKKβ in A547 and H2170 lung cancer cell lines effectively reduced the self-renewal and migration capability of NSCLC CSCs (98).

Cellular metabolism

Malignant transformation and tumor progression require the metabolic reprogramming of cancer cells for tumor growth and survival (99). Elucidating the emerging role that metabolism plays in cancer initiation and metastasis led to its incorporation into cancer hallmarks representing a possible therapeutic target (100). NF-κB has also been implicated in metabolic reprogramming. It has been documented that glutamine-fructose-6-phosphate transaminase 2, which is a rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine, is transcriptionally upregulated by NF-κB in NSCLC, linking cancer metabolism with tumor promotion (101). Furthermore, NF-κB tumor protein expression has positively been associated with tumor glucose uptake on 18F-fluorodeoxyglucose positron emission tomography in patients with NSCLC (102).

Treatment resistance

Another aspect of the multifaceted role of NF-κB in lung cancer is its contribution to treatment resistance. The constitutive activation of NF-κB signaling has been associated with increased resistance to chemotherapy as well as to radiotherapy. Chuang and colleagues have reported evidence that cellular sensitivity to chemotherapeutics (e.g., cisplatin and paclitaxel) can be inversely related to the baseline NF-κB activity based on data derived from cell lines (including the H460 cell line; ref. 103). In addition, Goldwin and colleagues have documented that lung cancer cells with resistance to cisplatin have an increased expression of NF-κB in comparison with cisplatin-sensitive cells, suggesting that NF-κB contributes to the acquisition of cisplatin resistance (104). In addition, overexpression of manganese superoxide dismutase has been associated with cisplatin resistance in lung adenocarcinoma, which is mediated by the NF-κB/BCL2/Snail pathway (105). Cytoplasmic detection of RAP1 (Ras-related protein Rap-1A), another positive regulator of NF-κB signaling, has also been correlated with cisplatin resistance of NSCLC through the activation of NF-κB/BCL2 axis (106).

In this context, a study conducted two decades ago by Jones and colleagues provided evidence that treatment with gemcitabine in vitro induced NF-κB activation, whereas inhibition of NF-κB increased apoptosis of H157 lung cancer cells, suggesting that NF-κB is required for cell survival after chemotherapy (64). Similarly, Denlinger and colleagues showed in vitro and in vivo that targeting the proteasome with bortezomib inhibited gemcitabine-induced activation of NF-κB and therefore increased sensitization of NSCLC to cell death (107). Moreover, targeted inhibition of NF-κB in cisplatin-resistant NSCLC cells may block the expression of P-glycoprotein, which is responsible for multidrug resistance (108, 109). Of particular note, binding sites for NF-κB have been identified in the human multidrug resistance gene 1 (MDR1; ref. 110). Furthermore, in the aforementioned work of Denlinger and colleagues, it has been shown that treatment with gemcitabine induces the transcription of selected antiapoptotic genes, such as a cellular inhibitor of apoptosis protein 2 and B-cell lymphoma extra-large, through the activation of NF-κB (107).

The NF-κB pathway has also been associated with resistance to paclitaxel of A549 lung adenocarcinoma cells. On the other hand, Jiang and colleagues found that triptolide, a natural drug with anticancer activity and many reported targets, reverses paclitaxel resistance inhibiting the NF-κB pathway (111).

Our knowledge is limited about the role of NF-κB in NSCLC, which bears driver gene mutations, as evidence is mainly derived from in vivo research models. However, the presence of mutated driver genes (EGFR, KRAS, and PI3K) in lung cancer epithelial cells seems to have a close interplay with NF-κB. In particular, Blakely and colleagues documented that EGFR inhibition in lung cancer leads to NF-κB signaling activation through the formation of the EGFR–TRAF2–RIP1–IKK activating complex, which promotes NF-κB–mediated tumor cell survival (112). Later, Pan and colleagues, using a transgenic mouse model, showed that mucosa-associated lymphoid tissue 1 protein is implicated in EGFR-induced NF-κB activation, recruiting E3 ligase TRAF6 to the IKK complex after EGF stimulation (113). In addition, in a mouse model with mutated EGFR lung tumors, Saxon and colleagues demonstrated the close connection of NF-κB between epithelial cells and protumorigenic macrophages, which is believed to contribute to the formation of a protumorigenic inflammatory microenvironment (114). NF-κB has also been associated with a response to targeted treatments against EGFR, a close relationship that is described below.

In addition, as for EGFR status, it seems that NF-κB is also necessary for the action of mutated GTPase KRas (KRAS), which are tumor-promoting proteins. The presence of KRAS mutations has been found to be related to IKKβ activity and the activation of the NF-κB classical pathway (115, 116). Furthermore, Vreka and colleagues confirmed that IKKα cooperates with mutant KRAS and is required for KRAS-mutated lung adenocarcinoma initiation and tumor progression (117). Also, it has been shown that IKKβ promotes KRAS-mutant tumor growth and angiogenesis in a lung cancer cell line (80). Interestingly, PD-L1 expression in KRAS-mutated NSCLC is also regulated through NF-κB and HIF1α pathways (118).

PI3K is another key molecule in lung cancer, which participates in the PI3K/Akt signaling pathway and is usually mutated in NSCLC (119). PIK3CA amplification and mutations have been reported more frequently in squamous cell cancers compared with lung adenocarcinomas (119, 120). One of the most important signaling components downstream to Akt is NF-κB (121). The next step after the activation of the PI3K/Akt pathway is the phosphorylation of IKKα. The latter phosphorylates IκB proteins, promoting their proteasomal degradation and resulting in nuclear translocation of NF-κB and transcription of prosurvival and antiapoptotic genes (122). Interestingly, Hutti and colleagues have shown, using breast cancer cells (MCF10A and THP-1), that growth factor deprivation leads oncogenic PI3K-mutated cells to encode mainly NF-κB–related secreted proteins, suggesting a paracrine and tumor microenvironment manipulating role (123). Similar data do not yet exist for NSCLC.

NF-κB has been characterized as a master regulator not only of inflammation but also of influencing the immune response (37, 124). Most of the studies on NF-κB have focused on its role in epithelial malignant cells per se, and little is known regarding its role in the formation of the tumor immune contexture. It seems that NF-κB is a key component and regulator within the tumor microenvironment, and its role has been described extensively elsewhere (125). Hopewell and colleagues have shown, in murine and human lung cancer, that antitumor T-cell responses are associated with tumorous NF-κB activity, which mediates immune surveillance (46). Furthermore, using an endogenous lung cancer model, Li and colleagues have shown that intrinsic RelA drives TAMs to suppress cytotoxic T lymphocytes via the induction of inhibitory molecule B7x (B7-H4/B7S1) expression in TAMs directly and changing T-cell suppressive cytokine IL10 (126). Li and colleagues have suggested that the dysfunction of dendritic cells, which has been observed in patients with NSCLC and which exerts a crucial role in cancer immune evasion, might be the result of simultaneous suppression of STAT3 and NF-κB signaling in dendritic cells (127).

The overall expression of NF-κB family members has become associated with the clinical outcome of patients with lung cancer, with more studies focusing on the clinical value of RelA. Key findings from published studies are presented in Supplementary Table S1, noting the change in the expression levels as well as any clinical significance from each paper. Two years ago, a meta-analysis, which was conducted by Gu and colleagues and characterized by significant heterogeneity between selected studies, showed that increased NF-κB expression was associated with shorter overall survival (OS) of patients with NSCLC. In addition, the level of NF-κB expression was also correlated with tumor stage and lymph node infiltration. In this meta-analysis, seven studies were reviewed, and prognostic significance focused on their cellular localization (cytoplasm-nucleus) was examined with regards to RelA, RelB, and NF-κB1 (p105 and p50; ref. 128). Although subcellular localization of NF-κB in the nucleus is usually considered to be the only functional sign of this pathway activation, however, cytoplasmic detection of the NF-κB component has also been associated with the clinical outcome, reflecting potent and different mechanisms of function.

NF-κB1

NF-κB1 (p105) has been associated with longer survival because a higher cytoplasmic tumor epithelial cell expression of NF-κB1 is correlated with a positive prognostic significance and longer disease-specific survival (DSS). In addition, the same group also found that the stromal cell expression of NF-κB p105 was also related to DSS (129). On the contrary, in an earlier study, in which 71 patients were enrolled, nuclear NF-κB (p50) overexpression was found to be associated with shorter survival (130), a discrepancy probably due to different subcellular localization.

NF-κB2

Data on NF-κB2 and its clinical significance in NSCLC are limited. Our group has shown that NF-κB2 is correlated with poor prognosis for patients with stage I lung cancer and no lymph node infiltration (131). Other studies have shown that, in patients with N2 disease, stromal p100/p52 expression was decreased compared with patients without lymphatic infiltration (132). Furthermore, Saxon and colleagues demonstrated that overexpression of p52 in human lung adenocarcinomas is a common phenomenon and that higher expression of p52-associated genes is associated with a negative prognosis (133).

RelA

Regarding RelA, increased IHC expression of RelA has been associated with lower median survival time (134). In addition, in stages I and II, nuclear RelA has been found to be increased compared with adjacent normal tissue and normal lung tissue, whereas it was inversely associated with poor prognosis (135, 136). In another study, Tang and colleagues conducted an IHC analysis in 394 patients with lung cancer (370 NSCLC, 24 SCLC, and 269 lung normal epithelium and preneoplastic lesions) showing that RelA can be detected in significantly higher levels in SCLCs compared with NSCLCs, whereas, in adenocarcinomas, RelA expression can be significantly higher in advanced tumor–node–metastasis stages (III–IV) than in earlier stages (I–II; ref. 137). Similarly, Nair and colleagues found in a cohort of 355 patients with higher cytoplasmic RelA that the expression was marginally associated with a shorter OS. Increased levels of both RelA and lactate dehydrogenase-A expression were synergistic and associated with both recurrence and shorter survival (102). In addition, Yu and colleagues have shown that overexpression of nuclear p65 has been associated with significantly poorer OS and DFS in a group of 115 patients with surgically resected lung adenocarcinoma (138). In another study from Abo El-Magd and colleagues, which evaluated RelA expression by IHC in a small group of patients, RelA expression emerged with a strong prognostic value for survival of patients with lung adenocarcinoma (139).

RelB

There are also some limited data on the clinical significance of RelB expression in lung cancer. A recent study showed that patients with NSCLC with higher cytoplasmic RelB expression had significantly shorter OS than patients with lower RelB expression (140). In addition to this publication, our group has recently published clinical data on RelB expression in primary NSCLC lesions, in which RelB overexpression (both in protein cytoplasmic and mRNA level) was associated with poor 5-year clinical outcomes (131).

c-Rel

Data on the role of c-Rel in cancer development are primarily derived from hematologic malignancies, because its significance in solid tumors is not well explored (141). Although c-Rel has been characterized in breast, head and neck, and pancreatic cancers, no translational studies have been conducted regarding its clinical significance in patients with NSCLC (142–145).

Many studies have reported on the clinical significance of genetic variations of NF-κB, mainly in Chinese and Caucasian populations, and are summarized in Supplementary Table S2. In a small study (95 patients with NSCLC and 99 healthy controls), NF-κB1 -94ins/delATTG was associated with an increased risk for NSCLC (3.5-fold change; ref. 146). In a bigger cohort (1,559 cases of lung cancer and 1,679 cancer-free controls), in which NF-κB1 -94ins/delATTG was also assessed in individuals with pre-existing chronic obstructive pulmonary disease, this specific SNP was associated with an increased risk of lung cancer (147). However, no association was found between the same SNP and risk of lung cancer in another study, which included 544 Chinese patients with lung cancer and 550 matched controls who were cancer-free (matched for age, sex, and ethnicity; ref. 148). In the study by Yin and colleagues, five other genetic variations (rs3774934, rs13117745, rs230541, rs1801, and rs3774965) of NF-κB1 were studied in 384 Chinese patients with lung cancer and 387 controls who were cancer-free. Interestingly, the haplotype consisting of the alleles rs3774934G, rs13117745C, rs230541A, and rs1801G was associated with lung cancer risk (149). Regarding the SNPs of NF-κB1, rs4648127 was found to be associated with lung adenocarcinoma, among 1,429 genes that were analyzed in 378 patients with lung cancer and 450 controls, most of whom were Caucasian (150).

Our group recently published a study in which the clinical relevance of NF-κB2 SNPs rs7897947, rs11574852, and rs12769316 was evaluated in a Caucasian population with NSCLC. Interestingly, rs7897947 and rs12769316 were strongly associated with the risk of NSCLC. In addition, rs7897947 was associated with survival outcome, and rs12769316 was related to metastasis risk and prognosis of patients treated with chemotherapy (151). However, in the study by Huang and colleagues in a Chinese population, no association was found between rs12769316 and NSCLC risk (147). Apart from variations in NF-κB1 and NF-κB2 genes, an SNP of RELB has been studied in lung cancer. He and colleagues showed, in a Chinese Han population, that rs28372683 in combination with SNPs of Inhibitor of nuclear factor kappa B kinase subunit epsilon and NF-kappa-B inhibitor alpha were associated with the prognosis of lung cancer (152).

There is evidence that the activity of NF-κB affects the efficacy of the treatment administered to patients with lung cancer, and this explains why NF-κB is a potential target for pharmacologic intervention. In this section, we will present published studies on the role of NF-κB in the treatment of patients with NSCLC using chemotherapy, targeted therapies, and immunotherapy.

Chemotherapy

NF-κB activation has been associated with resistance to chemotherapeutics. Data from preclinical models have shown that treatment with gemcitabine induces NF-κB nuclear translocation and DNA binding, whereas in vitro experiments inhibiting NF-κB sensitized NSCLC to chemotherapy (64) through a mitochondrial-mediated process, in which cytochrome c release and caspase-3 and -9 activations were implicated (153). In addition, Yang and colleagues have shown that deficient p53 and mutated KRAS cooperate with RelA in order to promote chemoresistance and tumorigenesis (154). Furthermore, enhanced NF-κB activation has been related to the stem-like phenotype of NSCLC and especially CSCs (98), whereas cisplatin-resistant A549 and H157 cell lines are characterized by increased stemness (155). In addition, it has been shown that NF-κB inhibition has overcome cisplatin resistance in NSCLC (156, 157).

Targeted therapies

EGFR TKIs

One of the most successful medical interventions in the management of NSCLC is the exploitation and targeting of mutated EGFR, using selective small-molecule TKIs (158). It has been suggested that NF-κB activation, in response to an EGFR blockade, promotes the survival of tumor cells (112), whereas many studies have linked NF-κB activation with resistance to TKI in EGFR-mutant lung cancer.

In a 3D EGFR-mutant lung adenocarcinoma cell culture model, Sakuma and colleagues showed that NF-κB (RelA) is associated with resistance to EGFR TKI–induced apoptosis, whereas inhibition of NF-κB can reverse this phenomenon (159). Supportive of this association was the observation that patients with EGFR-mutant lung carcinomas and low IκB expression had worse progression-free survival and decreased OS when they were treated with erlotinib (160). In addition, acquired resistance to TKIs has been linked to activation of NF-κB in human adenocarcinoma PC-9 cells, which is a very preliminary event, happening immediately after TKI initial administration as well as after EGFR gene silencing (161). Furthermore, by using A549 p53-knockdown cancer cells, Wu and colleagues documented that Aurora-A, a kinase essential for cell proliferation, mediates gefitinib resistance through the activation of NF-κB, a phenomenon that can be reversed by knocking down Aurora-A (162).

On the contrary, other studies suggest that NF-κB/RelA inhibition bypasses resistance to TKIs, such as erlotinib (163). Similarly, additional in vitro studies have reported that the inhibition of NF-κB signaling can bypass resistance to combined administration of irradiation and EGFR TKIs, diminishing concurrently induced lung toxicity (164). In addition, coadministration of metformin with rociletinib, a third-generation EGFR TKI, multiplies antitumor activity via the suppression of NF-κB signaling (165).

One of the major clinical problems in the management of patients with activating EGFR mutations, who are treated with TKIs, is the emergence of acquired resistance, which mostly is caused by a secondary mutation EGFR-T790M (166). Interestingly, it seems that NF-κB also subverts the efficacy of third-generation EGFR inhibitors. Galvani and colleagues documented that NF-κB drives acquired resistance to EGFR TKI CNX-2006, which is a mutant-selective, next-generation EGFR inhibitor, in the presence of the T790M mutation (167).

Many mechanisms through which NF-κB can mediate the resistance to TKIs have been suggested. Recently, Wang and colleagues reported that NF-κB (p50) can influence resistance to erlotinib through the reduction of miR-590 expression, which increases the expression of EH domain-containing protein 1 and in turn increases resistance to erlotinib and stemness of cancer cell (168). Another interesting observation was that gefitinib downregulates PD-L1 expression in EGFR-mutant NSCLC through inhibiting the NF-κB pathway (169). In addition, NF-κB orchestrates gefitinib resistance through transcriptional regulation of miR-155, which leads to a repression of FOXO3a, a transcription factor of the forkhead family (170).

Other inhibitors

The pharmacologic significance of NF-κB is not limited to TKIs and chemotherapy. It seems that NF-κB also influences the efficacy of other drugs as well. For instance, HDAC6 inhibits invasion by suppressing NF-κB/MMP2 (87), whereas the dual inhibition of histone deacetylase and NF-κB sensitizes NSCLC to cell death (171), possibly through induction of extrinsic apoptosis and generation of reactive oxygen species (172). In addition, it has been shown that NF-κB exerts a protective role in cancer cells that are treated with inhibitors of fatty acid synthase (173).

Immunotherapy

The central role of NF-κB in the formation of immunologic compartment of NSCLC has been studied for many years; however, we need to better understand the interaction of tumor cells with their microenvironment and the role of NF-κB in the development of the tumor-immune microenvironment. To this end, Hopewell and colleagues have reported that NF-κB activity in murine and human lung cancer mediates immune surveillance and is related to antitumor T-cell infiltration (46). Another interesting study noted is that PD-L1, which is upregulated during EMT, is regulated by both DNA methylation and NF-κB in NSCLC, implicating NF-κB in the effectiveness of checkpoint inhibitors against PD-1/PD-L1 axis (92).

It is clear that NF-κB orchestrates a very complicated system and plays a key role in cancer initiation and progression, providing a protective shield for malignant cells. A tremendous number of studies, which have shed light on its role in cancer, have shared encouraging results that NF-κB may clinically be transformed from an undruggable target to a novel treatment breakthrough, multiplying the potential of the current treating options and substantially improving our ability to target cancer cells.

H.P. Kalofonos reports grants from EOGE-Oncological funds during the conduct of the study. No potential conflicts of interest were disclosed by the other authors.

1.
Sen
R
,
Baltimore
D
. 
Multiple nuclear factors interact with the immunoglobulin enhancer sequences
.
Cell
1986
;
46
:
705
16
.
2.
Zhang
Q
,
Lenardo
MJ
,
Baltimore
D
. 
30 Years of NF-kappaB: a blossoming of relevance to human pathobiology
.
Cell
2017
;
168
:
37
57
.
3.
Celebrating 25 years of NF-kappaB
.
Nat Immunol
2011
;
12
:
681
.
4.
Pahl
HL
. 
Activators and target genes of Rel/NF-kappaB transcription factors
.
Oncogene
1999
;
18
:
6853
66
.
5.
Perkins
ND
,
Gilmore
TD
. 
Good cop, bad cop: the different faces of NF-kappaB
.
Cell Death Differ
2006
;
13
:
759
72
.
6.
Claudio
E
,
Brown
K
,
Siebenlist
U
. 
NF-kappaB guides the survival and differentiation of developing lymphocytes
.
Cell Death Differ
2006
;
13
:
697
701
.
7.
Escarcega
RO
,
Fuentes-Alexandro
S
,
Garcia-Carrasco
M
,
Gatica
A
,
Zamora
A
. 
The transcription factor nuclear factor-kappa B and cancer
.
Clin Oncol-Uk
2007
;
19
:
154
61
.
8.
Kucharczak
J
,
Simmons
MJ
,
Fan
Y
,
Gelinas
C
. 
To be, or not to be: NF-kappaB is the answer–role of Rel/NF-kappaB in the regulation of apoptosis
.
Oncogene
2003
;
22
:
8961
82
.
9.
Okamoto
T
,
Sanda
T
,
Asamitsu
K
. 
NF-kappa B signaling and carcinogenesis
.
Curr Pharm Design
2007
;
13
:
447
62
.
10.
Karin
M
,
Lin
A
. 
NF-kappaB at the crossroads of life and death
.
Nat Immunol
2002
;
3
:
221
7
.
11.
Aggarwal
BB
. 
Nuclear factor-kappaB: the enemy within
.
Cancer Cell
2004
;
6
:
203
8
.
12.
Vallabhapurapu
S
,
Karin
M
. 
Regulation and function of NF-kappaB transcription factors in the immune system
.
Annu Rev Immunol
2009
;
27
:
693
733
.
13.
Liu
T
,
Zhang
L
,
Joo
D
,
Sun
SC
. 
NF-kappaB signaling in inflammation
.
Signal Transduct Target Ther
2017
;
2
:
17023
.
14.
Oeckinghaus
A
,
Ghosh
S
. 
The NF-kappaB family of transcription factors and its regulation
.
Cold Spring Harb Perspect Biol
2009
;
1
:
a000034
.
15.
Anto
RJ
,
Mukhopadhyay
A
,
Shishodia
S
,
Gairola
CG
,
Aggarwal
BB
. 
Cigarette smoke condensate activates nuclear transcription factor-kappa B through phosphorylation and degradation of I kappa B alpha: correlation with induction of cyclooxygenase-2
.
Carcinogenesis
2002
;
23
:
1511
8
.
16.
Ahn
KS
,
Aggarwal
BB
. 
Transcription factor NF-kappaB: a sensor for smoke and stress signals
.
Ann N Y Acad Sci
2005
;
1056
:
218
33
.
17.
Gilmore
TD
,
Herscovitch
M
. 
Inhibitors of NF-kappaB signaling: 785 and counting
.
Oncogene
2006
;
25
:
6887
99
.
18.
Baud
V
,
Karin
M
. 
Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls
.
Nat Rev Drug Discovery
2009
;
8
:
33
40
.
19.
Bonizzi
G
,
Karin
M
. 
The two NF-kappa B activation pathways and their role in innate and adaptive immunity
.
Trends Immunol
2004
;
25
:
280
8
.
20.
Ravi
R
,
Bedi
A
. 
NF-kappaB in cancer–a friend turned foe
.
Drug Resist Updat
2004
;
7
:
53
67
.
21.
Hoffmann
A
,
Natoli
G
,
Ghosh
G
. 
Transcriptional regulation via the NF-kappaB signaling module
.
Oncogene
2006
;
25
:
6706
16
.
22.
Wietek
C
,
O'Neill
LA
. 
Diversity and regulation in the NF-kappaB system
.
Trends Biochem Sci
2007
;
32
:
311
9
.
23.
Dejardin
E
. 
The alternative NF-kappa B pathway from biochemistry to biology: pitfalls and promises for future drug development
.
Biochem Pharmacol
2006
;
72
:
1161
79
.
24.
Hoesel
B
,
Schmid
JA
. 
The complexity of NF-kappaB signaling in inflammation and cancer
.
Mol Cancer
2013
;
12
:
86
.
25.
Sun
SC
. 
Non-canonical NF-kappaB signaling pathway
.
Cell Res
2011
;
21
:
71
85
.
26.
Sun
SC
. 
The noncanonical NF-kappaB pathway
.
Immunol Rev
2012
;
246
:
125
40
.
27.
Sun
SC
,
Ley
SC
. 
New insights into NF-kappaB regulation and function
.
Trends Immunol
2008
;
29
:
469
78
.
28.
Nishina
T
,
Yamaguchi
N
,
Gohda
J
,
Semba
K
,
Inoue
J
. 
NIK is involved in constitutive activation of the alternative NF-kappaB pathway and proliferation of pancreatic cancer cells
.
Biochem Biophys Res Commun
2009
;
388
:
96
101
.
29.
Sun
SC
. 
Controlling the fate of NIK: a central stage in noncanonical NF-kappaB signaling
.
Sci Signal
2010
;
3
:
pe18
.
30.
Sun
SC
. 
The non-canonical NF-kappaB pathway in immunity and inflammation
.
Nat Rev Immunol
2017
;
17
:
545
58
.
31.
Tegowski
M
,
Baldwin
A
. 
Noncanonical NF-kappaB in cancer
.
Biomedicines
2018
;
6
:
66
.
32.
Xia
L
,
Tan
S
,
Zhou
Y
,
Lin
J
,
Wang
H
,
Oyang
L
, et al
Role of the NFkappaB-signaling pathway in cancer
.
OncoTarget Ther
2018
;
11
:
2063
73
.
33.
Bharti
AC
,
Aggarwal
BB
. 
Nuclear factor-kappa B and cancer: its role in prevention and therapy
.
Biochem Pharmacol
2002
;
64
:
883
8
.
34.
Wang
CY
,
Cusack
JC
 Jr.
,
Liu
R
,
Baldwin
AS
 Jr.
Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB
.
Nat Med
1999
;
5
:
412
7
.
35.
Pikarsky
E
,
Ben-Neriah
Y
. 
NF-kappaB inhibition: a double-edged sword in cancer?
Eur J Cancer
2006
;
42
:
779
84
.
36.
Ben-Neriah
Y
,
Karin
M
. 
Inflammation meets cancer, with NF-kappaB as the matchmaker
.
Nat Immunol
2011
;
12
:
715
23
.
37.
DiDonato
JA
,
Mercurio
F
,
Karin
M
. 
NF-kappaB and the link between inflammation and cancer
.
Immunol Rev
2012
;
246
:
379
400
.
38.
Grivennikov
SI
,
Greten
FR
,
Karin
M
. 
Immunity, inflammation, and cancer
.
Cell
2010
;
140
:
883
99
.
39.
Xiao
Z
,
Jiang
Q
,
Willette-Brown
J
,
Xi
S
,
Zhu
F
,
Burkett
S
, et al
The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas
.
Cancer Cell
2013
;
23
:
527
40
.
40.
Xia
Y
,
Yeddula
N
,
Leblanc
M
,
Ke
E
,
Zhang
Y
,
Oldfield
E
, et al
Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model
.
Nat Cell Biol
2012
;
14
:
257
65
.
41.
Meylan
E
,
Dooley
AL
,
Feldser
DM
,
Shen
L
,
Turk
E
,
Ouyang
C
, et al
Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma
.
Nature
2009
;
462
:
104
7
.
42.
Stathopoulos
GT
,
Sherrill
TP
,
Cheng
DS
,
Scoggins
RM
,
Han
W
,
Polosukhin
VV
, et al
Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis
.
PNAS
2007
;
104
:
18514
9
.
43.
Li
E
,
Xu
Z
,
Zhao
H
,
Sun
Z
,
Wang
L
,
Guo
Z
, et al
Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-kappaB and STAT3 signaling in a bionic airway chip culture and in animal models
.
Oncotarget
2015
;
6
:
8900
13
.
44.
Zaynagetdinov
R
,
Stathopoulos
GT
,
Sherrill
TP
,
Cheng
DS
,
McLoed
AG
,
Ausborn
JA
, et al
Epithelial nuclear factor-kappaB signaling promotes lung carcinogenesis via recruitment of regulatory T lymphocytes
.
Oncogene
2012
;
31
:
3164
76
.
45.
Takahashi
H
,
Ogata
H
,
Nishigaki
R
,
Broide
DH
,
Karin
M
. 
Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation
.
Cancer Cell
2010
;
17
:
89
97
.
46.
Hopewell
EL
,
Zhao
W
,
Fulp
WJ
,
Bronk
CC
,
Lopez
AS
,
Massengill
M
, et al
Lung tumor NF-kappaB signaling promotes T cell-mediated immune surveillance
.
J Clin Invest
2013
;
123
:
2509
22
.
47.
Deng
J
,
Fujimoto
J
,
Ye
XF
,
Men
TY
,
Van Pelt
CS
,
Chen
YL
, et al
Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis
.
Cancer Prev Res
2010
;
3
:
424
37
.
48.
Londhe
VA
,
Nguyen
HT
,
Jeng
JM
,
Li
X
,
Li
C
,
Tiozzo
C
, et al
NF-kB induces lung maturation during mouse lung morphogenesis
.
Dev Dyn
2008
;
237
:
328
38
.
49.
Muraoka
RS
,
Bushdid
PB
,
Brantley
DM
,
Yull
FE
,
Kerr
LD
. 
Mesenchymal expression of nuclear factor-kappaB inhibits epithelial growth and branching in the embryonic chick lung
.
Dev Biol
2000
;
225
:
322
38
.
50.
Iosef
C
,
Alastalo
TP
,
Hou
Y
,
Chen
C
,
Adams
ES
,
Lyu
SC
, et al
Inhibiting NF-kappaB in the developing lung disrupts angiogenesis and alveolarization
.
Am J Physiol Lung Cell Mol Physiol
2012
;
302
:
L1023
36
.
51.
Chen
W
,
Li
Z
,
Bai
L
,
Lin
Y
. 
NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target
.
Front Biosci
2011
;
16
:
1172
85
.
52.
Min
C
,
Eddy
SF
,
Sherr
DH
,
Sonenshein
GE
. 
NF-kappaB and epithelial to mesenchymal transition of cancer
.
J Cell Biochem
2008
;
104
:
733
44
.
53.
Cai
Z
,
Tchou-Wong
KM
,
Rom
WN
. 
NF-kappaB in lung tumorigenesis
.
Cancers
2011
;
3
:
4258
68
.
54.
Hussain
SP
,
Hofseth
LJ
,
Harris
CC
. 
Radical causes of cancer
.
Nat Rev Cancer
2003
;
3
:
276
85
.
55.
He
G
,
Karin
M
. 
NF-kappaB and STAT3 - key players in liver inflammation and cancer
.
Cell Res
2011
;
21
:
159
68
.
56.
Dougan
M
,
Li
D
,
Neuberg
D
,
Mihm
M
,
Googe
P
,
Wong
KK
, et al
A dual role for the immune response in a mouse model of inflammation-associated lung cancer
.
J Clin Invest
2011
;
121
:
2436
46
.
57.
Li
Y
,
Du
H
,
Qin
Y
,
Roberts
J
,
Cummings
OW
,
Yan
C
. 
Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung
.
Cancer Res
2007
;
67
:
8494
503
.
58.
Ho
YS
,
Chen
CH
,
Wang
YJ
,
Pestell
RG
,
Albanese
C
,
Chen
RJ
, et al
Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation
.
Toxicol Appl Pharmacol
2005
;
205
:
133
48
.
59.
Tang
H
,
Lv
W
,
Sun
W
,
Bi
Q
,
Hao
Y
. 
miR505 inhibits cell growth and EMT by targeting MAP3K3 through the AKTNFkappaB pathway in NSCLC cells
.
Int J Mol Med
2019
;
43
:
1203
16
.
60.
Zhou
W
,
Chen
X
,
Hu
Q
,
Chen
X
,
Chen
Y
,
Huang
L
. 
Galectin-3 activates TLR4/NF-kappaB signaling to promote lung adenocarcinoma cell proliferation through activating lncRNA-NEAT1 expression
.
BMC Cancer
2018
;
18
:
580
.
61.
Xu
L
,
Wu
Q
,
Zhou
X
,
Wu
Q
,
Fang
M
. 
TRIM13 inhibited cell proliferation and induced cell apoptosis by regulating NF-kappaB pathway in non-small-cell lung carcinoma cells
.
Gene
2019
;
715
:
144015
.
62.
Zhang
S
,
Yu
D
. 
PI(3)king apart PTEN's role in cancer
.
Clin Cancer Res
2010
;
16
:
4325
30
.
63.
Escriva
M
,
Peiro
S
,
Herranz
N
,
Villagrasa
P
,
Dave
N
,
Montserrat-Sentis
B
, et al
Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis
.
Mol Cell Biol
2008
;
28
:
1528
40
.
64.
Jones
DR
,
Broad
RM
,
Madrid
LV
,
Baldwin
AS
 Jr
,
Mayo
MW
. 
Inhibition of NF-kappaB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis
.
Ann Thorac Surg
2000
;
70
:
930
6
.
65.
Batra
RK
,
Lin
Y
,
Sharma
S
,
Dohadwala
M
,
Luo
J
,
Pold
M
, et al
Non-small cell lung cancer-derived soluble mediators enhance apoptosis in activated T lymphocytes through an I kappa B kinase-dependent mechanism
.
Cancer Res
2003
;
63
:
642
6
.
66.
Jackson
AL
,
Zhou
B
,
Kim
WY
. 
HIF, hypoxia and the role of angiogenesis in non-small cell lung cancer
.
Expert Opin Ther Targets
2010
;
14
:
1047
57
.
67.
Li
L
,
Li
JC
,
Yang
H
,
Zhang
X
,
Liu
LL
,
Li
Y
, et al
Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis
.
PNAS
2018
;
115
:
E8948
E57
.
68.
Sheng
J
,
Yang
Y
,
Ma
Y
,
Yang
B
,
Zhang
Y
,
Kang
S
, et al
The efficacy of combining antiangiogenic agents with chemotherapy for patients with advanced non-small cell lung cancer who failed first-line chemotherapy: a systematic review and meta-analysis
.
PLoS One
2015
;
10
:
e0127306
.
69.
Perdrizet
K
,
Leighl
NB
. 
The role of angiogenesis inhibitors in the era of immune checkpoint inhibitors and targeted therapy in metastatic non-small cell lung cancer
.
Curr Treat Options Oncol
2019
;
20
:
21
.
70.
Kiesgen
S
,
Chicaybam
L
,
Chintala
NK
,
Adusumilli
PS
. 
Chimeric antigen receptor (CAR) T-cell therapy for thoracic malignancies
.
J Thorac Oncol
2018
;
13
:
16
26
.
71.
Manzo
A
,
Montanino
A
,
Carillio
G
,
Costanzo
R
,
Sandomenico
C
,
Normanno
N
, et al
Angiogenesis Inhibitors in NSCLC
.
Int J Mol Sci
2017
;
18
:
2021
.
72.
Pircher
A
,
Wolf
D
,
Heidenreich
A
,
Hilbe
W
,
Pichler
R
,
Heidegger
I
. 
Synergies of targeting tumor angiogenesis and immune checkpoints in non-small cell lung cancer and renal cell cancer: from basic concepts to clinical reality
.
Int J Mol Sci
2017
;
18
;
2291
.
73.
Tabchi
S
,
Blais
N
. 
Antiangiogenesis for advanced non-small-cell lung cancer in the era of immunotherapy and personalized medicine
.
Front Oncol
2017
;
7
:
52
.
74.
Huang
S
,
Robinson
JB
,
Deguzman
A
,
Bucana
CD
,
Fidler
IJ
. 
Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8
.
Cancer Res
2000
;
60
:
5334
9
.
75.
Kimura
YN
,
Watari
K
,
Fotovati
A
,
Hosoi
F
,
Yasumoto
K
,
Izumi
H
, et al
Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis
.
Cancer Sci
2007
;
98
:
2009
18
.
76.
Rius
J
,
Guma
M
,
Schachtrup
C
,
Akassoglou
K
,
Zinkernagel
AS
,
Nizet
V
, et al
NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha
.
Nature
2008
;
453
:
807
11
.
77.
Cummins
EP
,
Berra
E
,
Comerford
KM
,
Ginouves
A
,
Fitzgerald
KT
,
Seeballuck
F
, et al
Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity
.
PNAS
2006
;
103
:
18154
9
.
78.
Walmsley
SR
,
Print
C
,
Farahi
N
,
Peyssonnaux
C
,
Johnson
RS
,
Cramer
T
, et al
Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity
.
J Exp Med
2005
;
201
:
105
15
.
79.
Belaiba
RS
,
Bonello
S
,
Zahringer
C
,
Schmidt
S
,
Hess
J
,
Kietzmann
T
, et al
Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells
.
Mol Biol Cell
2007
;
18
:
4691
7
.
80.
Carneiro-Lobo
TC
,
Scalabrini
LC
,
Magalhaes
LDS
,
Cardeal
LB
,
Rodrigues
FS
,
Dos Santos
EO
, et al
IKKbeta targeting reduces KRAS-induced lung cancer angiogenesis in vitro and in vivo: A potential anti-angiogenic therapeutic target
.
Lung Cancer
2019
;
130
:
169
78
.
81.
Stathopoulos
GT
,
Sherrill
TP
,
Han
W
,
Sadikot
RT
,
Yull
FE
,
Blackwell
TS
, et al
Host nuclear factor-kappaB activation potentiates lung cancer metastasis
.
Mol Cancer Res
2008
;
6
:
364
71
.
82.
Gao
M
,
Yeh
PY
,
Lu
YS
,
Chang
WC
,
Kuo
ML
,
Cheng
AL
. 
NF-kappaB p50 promotes tumor cell invasion through negative regulation of invasion suppressor gene CRMP-1 in human lung adenocarcinoma cells
.
Biochem Biophys Res Commun
2008
;
376
:
283
7
.
83.
Jiang
Y
,
Cui
L
,
Yie
TA
,
Rom
WN
,
Cheng
H
,
Tchou-Wong
KM
. 
Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta
.
Oncogene
2001
;
20
:
2254
63
.
84.
Huang
CY
,
Fong
YC
,
Lee
CY
,
Chen
MY
,
Tsai
HC
,
Hsu
HC
, et al
CCL5 increases lung cancer migration via PI3K, Akt and NF-kappaB pathways
.
Biochem Pharmacol
2009
;
77
:
794
803
.
85.
Fong
YC
,
Liu
SC
,
Huang
CY
,
Li
TM
,
Hsu
SF
,
Kao
ST
, et al
Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin/FAK/Akt and NF-kappaB-dependent pathway
.
Lung Cancer
2009
;
64
:
263
70
.
86.
Gong
WJ
,
Liu
JY
,
Yin
JY
,
Cui
JJ
,
Xiao
D
,
Zhuo
W
, et al
Resistin facilitates metastasis of lung adenocarcinoma through the TLR4/Src/EGFR/PI3K/NF-kappaB pathway
.
Cancer Sci
2018
;
109
:
2391
400
.
87.
Yang
CJ
,
Liu
YP
,
Dai
HY
,
Shiue
YL
,
Tsai
CJ
,
Huang
MS
, et al
Nuclear HDAC6 inhibits invasion by suppressing NF-kappaB/MMP2 and is inversely correlated with metastasis of non-small cell lung cancer
.
Oncotarget
2015
;
6
:
30263
76
.
88.
Chang
YW
,
Chiu
CF
,
Lee
KY
,
Hong
CC
,
Wang
YY
,
Cheng
CC
, et al
CARMA3 represses metastasis suppressor NME2 to promote lung cancer stemness and metastasis
.
Am J Respir Crit Care Med
2015
;
192
:
64
75
.
89.
Kumar
M
,
Allison
DF
,
Baranova
NN
,
Wamsley
JJ
,
Katz
AJ
,
Bekiranov
S
, et al
NF-kappaB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells
.
PLoS One
2013
;
8
:
e68597
.
90.
Zhao
Y
,
Xu
Y
,
Li
Y
,
Xu
W
,
Luo
F
,
Wang
B
, et al
NF-kappaB-mediated inflammation leading to EMT via miR-200c is involved in cell transformation induced by cigarette smoke extract
.
Toxicol Sci
2013
;
135
:
265
76
.
91.
Tian
B
,
Widen
SG
,
Yang
J
,
Wood
TG
,
Kudlicki
A
,
Zhao
Y
, et al
The NFkappaB subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells
.
J Biol Chem
2018
;
293
:
16528
45
.
92.
Asgarova
A
,
Asgarov
K
,
Godet
Y
,
Peixoto
P
,
Nadaradjane
A
,
Boyer-Guittaut
M
, et al
PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma
.
Oncoimmunology
2018
;
7
:
e1423170
.
93.
Guo
JY
,
Hsu
HS
,
Tyan
SW
,
Li
FY
,
Shew
JY
,
Lee
WH
, et al
Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner
.
Oncogene
2017
;
36
:
2457
71
.
94.
Shibue
T
,
Weinberg
RA
. 
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
.
Nat Rev Clin Oncol
2017
;
14
:
611
29
.
95.
Aponte
PM
,
Caicedo
A
. 
Stemness in cancer: stem cells, cancer stem cells, and their microenvironment
.
Stem Cells Int
2017
;
2017
:
5619472
.
96.
Rinkenbaugh
AL
,
Baldwin
AS
. 
The NF-kappaB pathway and cancer stem cells
.
Cells
2016
;
5
:
16
.
97.
Kaltschmidt
C
,
Banz-Jansen
C
,
Benhidjeb
T
,
Beshay
M
,
Forster
C
,
Greiner
J
, et al
A Role for NF-kappaB in organ specific cancer and cancer stem cells
.
Cancers
2019
;
11
:
655
.
98.
Zakaria
N
,
Mohd Yusoff
N
,
Zakaria
Z
,
Widera
D
,
Yahaya
BH
. 
Inhibition of NF-kappaB signaling reduces the stemness characteristics of lung cancer stem cells
.
Front Oncol
2018
;
8
:
166
.
99.
Boroughs
LK
,
DeBerardinis
RJ
. 
Metabolic pathways promoting cancer cell survival and growth
.
Nat Cell Biol
2015
;
17
:
351
9
.
100.
Hanahan
D
,
Weinberg
RA
. 
Hallmarks of cancer: the next generation
.
Cell
2011
;
144
:
646
74
.
101.
Szymura
SJ
,
Zaemes
JP
,
Allison
DF
,
Clift
SH
,
D'Innocenzi
JM
,
Gray
LG
, et al
NF-kappaB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer
.
Cell Commun Signal
2019
;
17
:
24
.
102.
Nair
VS
,
Gevaert
O
,
Davidzon
G
,
Plevritis
SK
,
West
R
. 
NF-kappaB protein expression associates with (18)F-FDG PET tumor uptake in non-small cell lung cancer: a radiogenomics validation study to understand tumor metabolism
.
Lung Cancer
2014
;
83
:
189
96
.
103.
Chuang
SE
,
Yeh
PY
,
Lu
YS
,
Lai
GM
,
Liao
CM
,
Gao
M
, et al
Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells
.
Biochem Pharmacol
2002
;
63
:
1709
16
.
104.
Godwin
P
,
Baird
AM
,
Heavey
S
,
Barr
MP
,
O'Byrne
KJ
,
Gately
K
. 
Targeting nuclear factor-kappa B to overcome resistance to chemotherapy
.
Front Oncol
2013
;
3
:
120
.
105.
Chen
PM
,
Cheng
YW
,
Wu
TC
,
Chen
CY
,
Lee
H
. 
MnSOD overexpression confers cisplatin resistance in lung adenocarcinoma via the NF-kappaB/Snail/Bcl-2 pathway
.
Free Radical Biol Med
2015
;
79
:
127
37
.
106.
Xiao
L
,
Lan
X
,
Shi
X
,
Zhao
K
,
Wang
D
,
Wang
X
, et al
Cytoplasmic RAP1 mediates cisplatin resistance of non-small cell lung cancer
.
Cell Death Dis
2017
;
8
:
e2803
.
107.
Denlinger
CE
,
Rundall
BK
,
Keller
MD
,
Jones
DR
. 
Proteasome inhibition sensitizes non-small-cell lung cancer to gemcitabine-induced apoptosis
.
Ann Thorac Surg
2004
;
78
:
1207
14
.
108.
Dolcet
X
,
Llobet
D
,
Pallares
J
,
Matias-Guiu
X
. 
NF-kB in development and progression of human cancer
.
Virchows Arch
2005
;
446
:
475
82
.
109.
Kong
W
,
Ling
X
,
Chen
Y
,
Wu
X
,
Zhao
Z
,
Wang
W
, et al
Hesperetin reverses Pglycoproteinmediated cisplatin resistance in DDPresistant human lung cancer cells via modulation of the nuclear factorkappaB signaling pathway
.
Int J Mol Med
2020
;
45
:
1213
24
.
110.
Lee
CH
,
Jeon
YT
,
Kim
SH
,
Song
YS
. 
NF-kappaB as a potential molecular target for cancer therapy
.
Biofactors
2007
;
29
:
19
35
.
111.
Jiang
N
,
Dong
XP
,
Zhang
SL
,
You
QY
,
Jiang
XT
,
Zhao
XG
. 
Triptolide reverses the Taxol resistance of lung adenocarcinoma by inhibiting the NF-kappaB signaling pathway and the expression of NF-kappaB-regulated drug-resistant genes
.
Mol Med Rep
2016
;
13
:
153
9
.
112.
Blakely
CM
,
Pazarentzos
E
,
Olivas
V
,
Asthana
S
,
Yan
JJ
,
Tan
I
, et al
NF-kappaB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer
.
Cell Rep
2015
;
11
:
98
110
.
113.
Pan
D
,
Jiang
C
,
Ma
Z
,
Blonska
M
,
You
MJ
,
Lin
X
. 
MALT1 is required for EGFR-induced NF-kappaB activation and contributes to EGFR-driven lung cancer progression
.
Oncogene
2016
;
35
:
919
28
.
114.
Saxon
JA
,
Sherrill
TP
,
Polosukhin
VV
,
Sai
J
,
Zaynagetdinov
R
,
McLoed
AG
, et al
Epithelial NF-kappaB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment
.
Oncoimmunology
2016
;
5
:
e1168549
.
115.
Basseres
DS
,
Ebbs
A
,
Levantini
E
,
Baldwin
AS
. 
Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis
.
Cancer Res
2010
;
70
:
3537
46
.
116.
Chen
W
,
Wang
X
,
Bai
L
,
Liang
X
,
Zhuang
J
,
Lin
Y
. 
Blockage of NF-kappaB by IKKbeta- or RelA-siRNA rather than the NF-kappaB super-suppressor IkappaBalpha mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells
.
J Cell Biochem
2008
;
105
:
554
61
.
117.
Vreka
M
,
Lilis
I
,
Papageorgopoulou
M
,
Giotopoulou
GA
,
Lianou
M
,
Giopanou
I
, et al
IkappaB kinase alpha is required for development and progression of KRAS-mutant lung adenocarcinoma
.
Cancer Res
2018
;
78
:
2939
51
.
118.
Guo
R
,
Li
Y
,
Bai
H
,
Wang
J
. 
KRAS mutants to regulate PD-L1 expression through NF-κB and HIF-1α pathways in non-small cell lung cancer cells
.
J Clin Oncol
2017
;
35
:
e20049
.
119.
Scheffler
M
,
Bos
M
,
Gardizi
M
,
Konig
K
,
Michels
S
,
Fassunke
J
, et al
PIK3CA mutations in non-small cell lung cancer (NSCLC): genetic heterogeneity, prognostic impact and incidence of prior malignancies
.
Oncotarget
2015
;
6
:
1315
26
.
120.
Spoerke
JM
,
O'Brien
C
,
Huw
L
,
Koeppen
H
,
Fridlyand
J
,
Brachmann
RK
, et al
Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models
.
Clin Cancer Res
2012
;
18
:
6771
83
.
121.
Kucuksayan
HH
. 
ASS. Pl3K/Akt/NF-κB signalling pathway on NSCLC invasion
.
Med Chem
2016
;
6
:
234
8
.
122.
Heavey
S
,
Godwin
P
,
Baird
AM
,
Barr
MP
,
Umezawa
K
,
Cuffe
S
, et al
Strategic targeting of the PI3K-NFkappaB axis in cisplatin-resistant NSCLC
.
Cancer Biol Ther
2014
;
15
:
1367
77
.
123.
Hutti
JE
,
Pfefferle
AD
,
Russell
SC
,
Sircar
M
,
Perou
CM
,
Baldwin
AS
. 
Oncogenic PI3K mutations lead to NF-kappaB-dependent cytokine expression following growth factor deprivation
.
Cancer Res
2012
;
72
:
3260
9
.
124.
Colomer
C
,
Marruecos
L
,
Vert
A
,
Bigas
A
,
Espinosa
L
. 
NF-kappaB members left home: NF-kappaB-independent roles in cancer
.
Biomedicines
2017
;
5
:
26
.
125.
Bao
B
,
Thakur
A
,
Li
Y
,
Ahmad
A
,
Azmi
AS
,
Banerjee
S
, et al
The immunological contribution of NF-kappaB within the tumor microenvironment: a potential protective role of zinc as an anti-tumor agent
.
Biochim Biophys Acta
2012
;
1825
:
160
72
.
126.
Li
L
,
Han
L
,
Sun
F
,
Zhou
J
,
Ohaegbulam
KC
,
Tang
X
, et al
NF-kappaB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8(+) T cells for tumor promotion
.
Oncoimmunology
2018
;
7
:
e1435250
.
127.
Li
R
,
Fang
F
,
Jiang
M
,
Wang
C
,
Ma
J
,
Kang
W
, et al
STAT3 and NF-kappaB are simultaneously suppressed in dendritic cells in lung cancer
.
Sci Rep
2017
;
7
:
45395
.
128.
Gu
L
,
Wang
Z
,
Zuo
J
,
Li
H
,
Zha
L
. 
Prognostic significance of NF-kappaB expression in non-small cell lung cancer: a meta-analysis
.
PLoS One
2018
;
13
:
e0198223
.
129.
Al-Saad
S
,
Al-Shibli
K
,
Donnem
T
,
Persson
M
,
Bremnes
RM
,
Busund
LT
. 
The prognostic impact of NF-kappaB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer
.
Br J Cancer
2008
;
99
:
1476
83
.
130.
Zhang
Z
,
Ma
J
,
Li
N
,
Sun
N
,
Wang
C
. 
Expression of nuclear factor-kappaB and its clinical significance in nonsmall-cell lung cancer
.
Ann Thorac Surg
2006
;
82
:
243
8
.
131.
Dimitrakopoulos
FD
,
Antonacopoulou
AG
,
Kottorou
AE
,
Panagopoulos
N
,
Kalofonou
F
,
Sampsonas
F
, et al
Expression of intracellular components of the NF-kappaB alternative pathway (NF-kappaB2, RelB, NIK and Bcl3) is associated with clinical outcome of NSCLC patients
.
Sci Rep
2019
;
9
:
14299
.
132.
Giopanou
I
,
Lilis
I
,
Papaleonidopoulos
V
,
Marazioti
A
,
Spella
M
,
Vreka
M
, et al
Comprehensive evaluation of nuclear factor-kappaBeta expression patterns in non-small cell lung cancer
.
PLoS One
2015
;
10
:
e0132527
.
133.
Saxon
JA
,
Yu
H
,
Polosukhin
VV
,
Stathopoulos
GT
,
Gleaves
LA
,
McLoed
AG
, et al
p52 expression enhances lung cancer progression
.
Sci Rep
2018
;
8
:
6078
.
134.
Abo El-Magd
GH
,
Abd El-Fattah
O
,
Saied
EM
. 
Immunohistochemical expression of nuclear factor kappa-B/p65 and cyclooxygenase-2 in non-small cell lung cancer patients: Prognostic value and impact on survival
.
Egypt J Chest Dis Tuberc
2014
;
63
:
193
200
.
135.
Zhang
D
,
Jin
X
,
Wang
F
,
Wang
S
,
Deng
C
,
Gao
Z
, et al
Combined prognostic value of both RelA and IkappaB-alpha expression in human non-small cell lung cancer
.
Ann Surg Oncol
2007
;
14
:
3581
92
.
136.
Jin
X
,
Wang
Z
,
Qiu
L
,
Zhang
D
,
Guo
Z
,
Gao
Z
, et al
Potential biomarkers involving IKK/RelA signal in early stage non-small cell lung cancer
.
Cancer Sci
2008
;
99
:
582
9
.
137.
Tang
X
,
Liu
D
,
Shishodia
S
,
Ozburn
N
,
Behrens
C
,
Lee
JJ
, et al
Nuclear factor-kappaB (NF-kappaB) is frequently expressed in lung cancer and preneoplastic lesions
.
Cancer
2006
;
107
:
2637
46
.
138.
Yu
J
,
Wang
L
,
Zhang
T
,
Shen
H
,
Dong
W
,
Ni
Y
, et al
Co-expression of beta-arrestin1 and NF-small ka, CyrillicB is associated with cancer progression and poor prognosis in lung adenocarcinoma
.
Tumour biology
2015
;
36
:
6551
8
.
139.
Abo El-Magd
GH
,
Abd El-Fattah
O
,
Saied
EM
. 
Immunohistochemical expression of nuclear factor kappa-B/p65 and cyclooxygenase-2 in non-small cell lung cancer patients: Prognostic value and impact on survival
.
Eur Respir J
2014
;
44
:
P512
.
140.
Qin
H
,
Zhou
J
,
Zhou
P
,
Xu
J
,
Tang
Z
,
Ma
H
, et al
Prognostic significance of RelB overexpression in non-small cell lung cancer patients
.
Thoracic Cancer
2016
;
7
:
415
21
.
141.
Hunter
JE
,
Leslie
J
,
Perkins
ND
. 
c-Rel and its many roles in cancer: an old story with new twists
.
Br J Cancer
2016
;
114
:
1
6
.
142.
Cogswell
PC
,
Guttridge
DC
,
Funkhouser
WK
,
Baldwin
AS
 Jr.
Selective activation of NF-kappaB subunits in human breast cancer: potential roles for NF-kappa B2/p52 and for Bcl-3
.
Oncogene
2000
;
19
:
1123
31
.
143.
Romieu-Mourez
R
,
Kim
DW
,
Shin
SM
,
Demicco
EG
,
Landesman-Bollag
E
,
Seldin
DC
, et al
Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors
.
Mol Cell Biol
2003
;
23
:
5738
54
.
144.
Geismann
C
,
Grohmann
F
,
Sebens
S
,
Wirths
G
,
Dreher
A
,
Hasler
R
, et al
c-Rel is a critical mediator of NF-kappaB-dependent TRAIL resistance of pancreatic cancer cells
.
Cell Death Dis
2014
;
5
:
e1455
.
145.
Lu
H
,
Yang
X
,
Duggal
P
,
Allen
CT
,
Yan
B
,
Cohen
J
, et al
TNF-alpha promotes c-REL/DeltaNp63alpha interaction and TAp73 dissociation from key genes that mediate growth arrest and apoptosis in head and neck cancer
.
Cancer Res
2011
;
71
:
6867
77
.
146.
Oltulu
YM
,
Coskunpinar
E
,
Ozkan
G
,
Aynaci
E
,
Yildiz
P
,
Isbir
T
, et al
Investigation of NF-κB1 and NF-κBIA gene polymorphism in non-small cell lung cancer
.
Biomed Res Int
2014
;
2014
:
6
.
147.
Huang
D
,
Yang
L
,
Liu
Y
,
Zhou
Y
,
Guo
Y
,
Pan
M
, et al
Functional polymorphisms in NFkappaB1/IkappaBalpha predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese
.
Hum Genet
2013
;
132
:
451
60
.
148.
Yin
J
,
Wang
H
,
Vogel
U
,
Wang
C
,
Hou
W
,
Ma
Y
. 
Association and interaction of NFKB1 rs28362491 insertion/deletion ATTG polymorphism and PPP1R13L and CD3EAP related to lung cancer risk in a Chinese population
.
Tumour Biol
2016
;
37
:
5467
73
.
149.
Yin
J
,
Yin
M
,
Vogel
U
,
Wu
Y
,
Yao
T
,
Cheng
Y
, et al
NFKB1 common variants and PPP1R13L and CD3EAP in relation to lung cancer risk in a Chinese population
.
Gene
2015
;
567
:
31
5
.
150.
Shiels
MS
,
Engels
EA
,
Shi
J
,
Landi
MT
,
Albanes
D
,
Chatterjee
N
, et al
Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk
.
Cancer
2012
;
118
:
5630
6
.
151.
Dimitrakopoulos
FD
,
Antonacopoulou
AG
,
Kottorou
AE
,
Maroussi
S
,
Panagopoulos
N
,
Koukourikou
I
, et al
NF-kB2 genetic variations are significantly associated with non-small cell lung cancer risk and overall survival
.
Sci Rep
2018
;
8
:
5259
.
152.
He
F
,
Yang
R
,
Li
XY
,
Ye
C
,
He
BC
,
Lin
T
, et al
Single nucleotide polymorphisms of the NF-kappaB and STAT3 signaling pathway genes predict lung cancer prognosis in a Chinese Han population
.
Cancer Genet
2015
;
208
:
310
8
.
153.
Jones
DR
,
Broad
RM
,
Comeau
LD
,
Parsons
SJ
,
Mayo
MW
. 
Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation
.
J Thorac Cardiovasc Surg
2002
;
123
:
310
7
.
154.
Yang
L
,
Zhou
Y
,
Li
Y
,
Zhou
J
,
Wu
Y
,
Cui
Y
, et al
Mutations of p53 and KRAS activate NF-kappaB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells
.
Cancer Lett
2015
;
357
:
520
6
.
155.
Zhang
F
,
Duan
S
,
Tsai
Y
,
Keng
PC
,
Chen
Y
,
Lee
SO
, et al
Cisplatin treatment increases stemness through upregulation of hypoxia-inducible factors by interleukin-6 in non-small cell lung cancer
.
Cancer Sci
2016
;
107
:
746
54
.
156.
Baird
AM
,
Godwin
P
,
Heavey
S
,
Umezawa
K
,
Barr
MP
,
Richard
D
, et al
Targeting NF-κB regulated pathways to overcome cisplatin resistance in non-small cell lung cancer
.
Lung Cancer
2014
;
83
:
S1
.
157.
Ryan
SL
,
Beard
S
,
Barr
MP
,
Umezawa
K
,
Heavey
S
,
Godwin
P
, et al
Targeting NF-kappaB-mediated inflammatory pathways in cisplatin-resistant NSCLC
.
Lung Cancer
2019
;
135
:
217
27
.
158.
Mayekar
MK
,
Bivona
TG
. 
Current landscape of targeted therapy in lung cancer
.
Clin Pharmacol Ther
2017
;
102
:
757
64
.
159.
Sakuma
Y
,
Yamazaki
Y
,
Nakamura
Y
,
Yoshihara
M
,
Matsukuma
S
,
Koizume
S
, et al
NF-kappaB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells
.
Biochem Biophys Res Commun
2012
;
423
:
667
71
.
160.
Bivona
TG
,
Hieronymus
H
,
Parker
J
,
Chang
K
,
Taron
M
,
Rosell
R
, et al
FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR
.
Nature
2011
;
471
:
523
6
.
161.
Fukuoka
M
,
Yoshioka
K
,
Hohjoh
H
. 
NF-kappaB activation is an early event of changes in gene regulation for acquiring drug resistance in human adenocarcinoma PC-9 cells
.
PLoS One
2018
;
13
:
e0201796
.
162.
Wu
CC
,
Yu
CT
,
Chang
GC
,
Lai
JM
,
Hsu
SL
. 
Aurora-A promotes gefitinib resistance via a NF-kappaB signaling pathway in p53 knockdown lung cancer cells
.
Biochem Biophys Res Commun
2011
;
405
:
168
72
.
163.
Blakely
CM
,
Olivas
V
,
Zhang
J
,
Bivona
TG
. 
Abstract 4631: Pharmacologic inhibition of NF-kappaB overcomes de novo resistance to erlotinib in models of EGFR-mutant lung adenocarcinoma
.
Cancer Res
2013
;
73
:
4631
-.
164.
Wang
R
,
Peng
S
,
Zhang
X
,
Wu
Z
,
Duan
H
,
Yuan
Y
, et al
Inhibition of NF-kappaB improves sensitivity to irradiation and EGFR-TKIs and decreases irradiation-induced lung toxicity
.
Int J Cancer
2019
;
144
:
200
9
.
165.
Pan
YH
,
Lin
CY
,
Lu
CH
,
Li
L
,
Wang
YB
,
Chen
HY
, et al
Metformin synergistically enhances the antitumor activity of the third-generation EGFR-TKI CO-1686 in lung cancer cells through suppressing NF-kappaB signaling
.
Clin Respir J
2018
;
12
:
2642
52
.
166.
Lim
SM
,
Syn
NL
,
Cho
BC
,
Soo
RA
. 
Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: mechanisms and therapeutic strategies
.
Cancer Treat Rev
2018
;
65
:
1
10
.
167.
Galvani
E
,
Sun
J
,
Leon
LG
,
Sciarrillo
R
,
Narayan
RS
,
Sjin
RT
, et al
NF-kappaB drives acquired resistance to a novel mutant-selective EGFR inhibitor
.
Oncotarget
2015
;
6
:
42717
32
.
168.
Wang
X
,
Yin
H
,
Zhang
H
,
Hu
J
,
Lu
H
,
Li
C
, et al
NF-kappaB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers
.
Cell Death Dis
2018
;
9
:
418
.
169.
Lin
K
,
Cheng
J
,
Yang
T
,
Li
Y
,
Zhu
B
. 
EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-kappaB
.
Biochem Biophys Res Commun
2015
;
463
:
95
101
.
170.
Chiu
CF
,
Chang
YW
,
Kuo
KT
,
Shen
YS
,
Liu
CY
,
Yu
YH
, et al
NF-kappaB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance
.
Proc Natl Acad Sci U S A
2016
;
113
:
E2526
35
.
171.
Rundall
BK
,
Denlinger
CE
,
Jones
DR
. 
Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death
.
Surgery
2004
;
136
:
416
25
.
172.
Karthik
S
,
Sankar
R
,
Varunkumar
K
,
Anusha
C
,
Ravikumar
V
. 
Blocking NF-κB sensitizes non-small cell lung cancer cells to histone deacetylase inhibitor induced extrinsic apoptosis through generation of reactive oxygen species
.
Biomed Pharmacother
2015
;
69
:
337
44
.
173.
Lemmon
CR
,
Woo
JH
,
Tully
E
,
Wilsbach
K
,
Gabrielson
E
. 
Nuclear factor-kappaB (NF-kappaB) mediates a protective response in cancer cells treated with inhibitors of fatty acid synthase
.
J Biol Chem
2011
;
286
:
31457
65
.