Gene Summary

Gene:NFKBIA; NFKB inhibitor alpha
Aliases: IKBA, MAD-3, NFKBI
Summary:This gene encodes a member of the NF-kappa-B inhibitor family, which contain multiple ankrin repeat domains. The encoded protein interacts with REL dimers to inhibit NF-kappa-B/REL complexes which are involved in inflammatory responses. The encoded protein moves between the cytoplasm and the nucleus via a nuclear localization signal and CRM1-mediated nuclear export. Mutations in this gene have been found in ectodermal dysplasia anhidrotic with T-cell immunodeficiency autosomal dominant disease. [provided by RefSeq, Aug 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:NF-kappa-B inhibitor alpha
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: NFKBIA (cancer-related)

Kim J, McMillan E, Kim HS, et al.
XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer.
Nature. 2016; 538(7623):114-117 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS-mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS-mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5-Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1-TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.

Kinker GS, Thomas AM, Carvalho VJ, et al.
Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.
Sci Rep. 2016; 6:24160 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas.

Carter SL, Carter SL, Centenera MM, et al.
IκBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor.
BMC Cancer. 2016; 16:141 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
BACKGROUND: Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, and the histone deacetylase inhibitor, vorinostat, act synergistically when combined to cause death of AR-dependent prostate cancer cells.
METHODS: In this study, expression profiling of human prostate cancer cells treated with bicalutamide or vorinostat, alone or in combination, was employed to determine the molecular mechanisms underlying this synergistic action. Cell viability assays and quantitative real time PCR were used to validate identified candidate genes.
RESULTS: A substantial proportion of the genes modulated by the combination of bicalutamide and vorinostat were androgen regulated. Independent pathway analysis identified further pathways and genes, most notably NFKBIA (encoding IκBα, an inhibitor of NF-κB and p53 signaling), as targets of this combinatorial treatment. Depletion of IκBα by siRNA knockdown enhanced apoptosis of prostate cancer cells, while ectopic overexpression of IκBα markedly suppressed cell death induced by the combination of bicalutamide and vorinostat.
CONCLUSION: These findings implicate IκBα as a key mediator of the apoptotic action of this combinatorial AR targeting strategy and a promising new therapeutic target for prostate cancer.

Fakhir FZ, Lkhider M, Badre W, et al.
The -94Ins/DelATTG polymorphism in NFκB1 promoter modulates chronic hepatitis C and liver disease progression.
Infect Genet Evol. 2016; 39:141-6 [PubMed] Related Publications
Infection with Hepatitis C Virus (HCV) is one of the most important risk factor of hepatocellular carcinoma (HCC). HCV is suspected to induce HCC primarily through chronic inflammation and promotion of cirrhosis, a well-known pre-neoplastic condition. The NF-κB pathway is a key regulator of immune and inflammatory processes and plays a pivotal role in oncogenesis. Genetic variations affecting the pathway may alter NF-κB activity in response to HCV infection and contribute to liver tumorigenesis. The present study aims to evaluate the association between -94Ins/DelATTG (rs28362491) polymorphism in NF-κB1 gene promoter region and 2758G>A (rs696) single nucleotide polymorphism in the 3'UTR region of NFκBIA and the outcomes of HCV infection. In this case-control study, 559 subjects (343 patients with HCV infection including 237 mild chronic hepatitis patients and 106 patients with Advanced Liver Disease (AdLD), 78 individuals who naturally cleared HCV and 138 healthy subjects) were genotyped for the NFκB1 and NFκBIA SNPs using PCR-RFLP. Logistic regression was used to assess the association between polymorphisms and the outcome and progression of the infection. Variation at rs696 was not associated with HCV resolution or progression (P>0.05). By contrast, the Ins/Ins genotype was associated with a 4-fold increase of AdLD risk when compared to mild chronic hepatitis C (OR=4.69; 95% CI, 2.15-10.19; P=0.0001) and the risk was more pronounced when compared to healthy controls (OR=5.02; 95% CI, 2.30-10.98; P=0.00005). Furthermore, carriage of Ins allele at rs28362491 was significantly associated with higher viral loads (P=0.003). Our results suggest that variation in NFκB1 gene promoter modulates the progression of chronic hepatitis C toward advanced liver disease.

Cui X, Yan H, Ou TW, et al.
Genetic Variations in Inflammatory Response Genes and Their Association with the Risk of Prostate Cancer.
Biomed Res Int. 2015; 2015:674039 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Prostate cancer is a common cancer in men. Genetic variations in inflammatory response genes can potentially influence the risk of prostate cancer. We aimed to examine the association between PPARG Pro12Ala, NFKB1 -94 ins/del, NFKBIA -826C/T, COX-1 (50C>T), and COX-2 (-1195G>A) polymorphisms on prostate cancer risk. The genotypes of the polymorphisms were ascertained in 543 prostate cancer patients and 753 controls through PCR-RFLP and the risk association was evaluated statistically using logistic regression analysis. The NFKB1 -94 polymorphism was shown to decrease prostate cancer risk in both heterozygous and homozygous comparison models (odds ratios of 0.74 (95% CI = 0.58-0.96) (P = 0.02) and 0.57 (95% CI = 0.42-0.78) (P < 0.01), resp.). An opposite finding was observed for COX-2 (-1195) polymorphism (odds ratios of 1.58 (95% CI = 1.15-2.18) (P < 0.01) for heterozygous comparison model and 2.08 (95% CI = 1.48-2.92) (P < 0.01) for homozygous comparison model). No association was observed for other polymorphisms. In conclusion, NFKB1 -94 ins/del and COX-2 (-1195G>A) polymorphisms may be, respectively, associated with decreased and increased prostate cancer risk in the Chinese population.

Shi Z, Hu Z, Chen D, et al.
MicroRNA-200a mediates nasopharyngeal carcinoma cell proliferation through the activation of nuclear factor-κB.
Mol Med Rep. 2016; 13(2):1732-8 [PubMed] Related Publications
In nasopharyngeal carcinoma (NPC), the nuclear factor-κB (NF-κB) signaling pathway is highly active. The constitutive activation of NF-κB prompts malignant cell proliferation, and microRNAs are considered an important mediator in regulating the NF-κB signaling pathway. The current study investigated the effect of microRNA-200a (miR-200a) on NF-κB activation. Reverse transcription-quantitative polymerase chain reaction was used to quantify the relative level of miR-200a in NPC tissue samples and CNE2 cells. An MTT assay was used to investigate the effect of miR-200a on cell proliferation. To investigate the activation of NF-κB, western blotting was used to measure the protein levels of NF-κB and its downstream targets. To identify the target genes of miR-200a, a luciferase reporter assay was used. The current study demonstrated that miR-200a was upregulated in NPC tissue samples and cell lines. Overexpression of miR-200a resulted in the proliferation of CNE2 cells. Western blot analysis indicated that the protein levels of p65 increased when CNE2 cells were transfected with miR-200a mimics. Additionally, the downstream targets of miR-200a were upregulated, including vascular cell adhesion molecule, intercellular adhesion molecule and monocyte chemoattractant protein-1. The luciferase assay indicated that IκBα was the target gene of miR-200a. In conclusion, miR-200a was demonstrated to enhance NPC cell proliferation by activating the NF-κB signaling pathway.

Griffin GK, Sholl LM, Lindeman NI, et al.
Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes.
Mod Pathol. 2016; 29(1):67-74 [PubMed] Related Publications
Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm with a variable and unpredictable clinical course. The genetic alterations that drive tumorigenesis in follicular dendritic cell sarcoma are largely unknown. One recent study performed BRAF sequencing and found V600E mutations in 5 of 27 (19%) cases. No other recurrent genetic alterations have been reported. The aim of the present study was to identify somatic alterations in follicular dendritic cell sarcoma by targeted sequencing of a panel of 309 known cancer-associated genes. DNA was isolated from formalin-fixed paraffin-embedded tissue from 13 cases of follicular dendritic cell sarcoma and submitted for hybrid capture-based enrichment and massively parallel sequencing with the Illumina HiSeq 2500 platform. Recurrent loss-of-function alterations were observed in tumor suppressor genes involved in the negative regulation of NF-κB activation (5 of 13 cases, 38%) and cell cycle progression (4 of 13 cases, 31%). Loss-of-function alterations in the NF-κB regulatory pathway included three cases with frameshift mutations in NFKBIA and two cases with bi-allelic loss of CYLD. Both cases with CYLD loss were metastases and carried concurrent alterations in at least one cell cycle regulatory gene. Alterations in cell cycle regulatory genes included two cases with bi-allelic loss of CDKN2A, one case with bi-allelic loss of RB1, and one case with a nonsense mutation in RB1. Last, focal copy-number gain of chromosome 9p24 including the genes CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-described mechanism of immune evasion in cancer. These findings provide the first insight into the unique genomic landscape of follicular dendritic cell sarcoma and suggest shared mechanisms of tumorigenesis with a subset of other tumor types, notably B-cell lymphomas.

Nam MS, Jung DB, Seo KH, et al.
Apoptotic Effect of Sanggenol L via Caspase Activation and Inhibition of NF-κB Signaling in Ovarian Cancer Cells.
Phytother Res. 2016; 30(1):90-6 [PubMed] Related Publications
In the present study, the underlying apoptotic mechanism of sanggenol L was elucidated in ovarian cancer cells. Sanggenol L showed cytotoxic and antiproliferative effect in A2780, SKOV-3, and OVCAR-3 ovarian cancer cells in a concentration-dependent fashion. Consistently, sanggenol L increased sub-G1 phase population and early and late apoptotic portion in ovarian cancer cells. Also, sanggenol L activated caspase9/3, suppressed the phosphorylation of IκBα and p65 NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), attenuated the expression of Cyclin D1, and cleaved poly(adenosine diphosphate ribose -ribose) polymerase in SKOV-3, A2780, and OVCAR-3 cells. Furthermore, sanggenol L blocked nuclear translocation of NF-κB and also attenuated the expression of NF-κB related genes such as c-Myc, Cyclin D1, and Bcl-X L, Bcl-2, in lipopolysaccharide-treated SKOV-3 cells. Overall, our findings for the first time suggest that sanggenol L induces apoptosis via caspase activation and inhibition of NF-κB/IκBα phosphorylation as a potent chemotherapeutic agent for ovarian cancers.

Rui LX, Shu SY, Jun WJ, et al.
The dual induction of apoptosis and autophagy by SZC014, a synthetic oleanolic acid derivative, in gastric cancer cells via NF-κB pathway.
Tumour Biol. 2016; 37(4):5133-44 [PubMed] Related Publications
Oleanolic acid (OA) possesses various pharmacological activities, such as antitumor and anti-inflammation; however, its clinical applications are limited by its relatively weak activities and low bioavailability. In this study, we evaluated the cytotoxic activity of seven novel OA derivatives, one of which, SZC014 [2-(pyrrolidine-1-yl) methyl-3-oxo-olean-12-en-28-oic acid], exhibited the strongest antitumor activity; its anticancer effect on gastric cancer cells and action mechanisms were investigated. The viability of OA and seven synthesized derivatives treating gastric cancer cells was detected using tetrazolium (MTT). Among them, SZC014 exhibited the strongest cytotoxic activity against gastric cancer cells (SGC7901, MGC803, and MKN-45). The effect of SZC014 on cell cycle was identified by propidium iodide (PI) staining assay. The cellular apoptosis induced by SZC014 was tested by annexin V/PI. The cellular morphological changes and ultrastructural structures affected by SZC014 were observed and imaged through inverted phase contrast microscope and transmission electron microscopy. Western blotting was performed to explore the expression of proteins associated with apoptosis (caspase 3, caspase 9, Bax, Bcl-2, and Bcl-xL), autophagy (Beclin 1 and ATG 5), and nuclear factor-κB (NF-κB) signal pathway, respectively. The cytotoxic activities of all the seven synthesized OA derivatives were stronger than that of OA against gastric cancer cells. SZC014 exhibited stronger cytotoxic activity than other OA derivatives, inhibited the proliferation of gastric cancer cells, besides, induced G2/M phase cell cycle arrest in SGC7901 cells. Both apoptosis and autophagy were found simultaneously in SZC014-treated SGC7901 cells. Caspase-dependent apoptosis induced by SZC014 was confirmed to be associated with upregulation of Bax and downregulation of Bcl-2 and Bcl-xL, while upregulation of Beclin 1 and ATG 5 was inferred to be involved in SZC014-induced autophagy. Moreover, treating cells with SZC014 resulted in a decrease in phosphorylation of IκBα and NF-κB/p65 and NF-κB/p65 nuclear translocation. The cytotoxic activities of seven OA derivatives were generally stronger than that of OA, among which, SZC014 possessed the most potent anticancer activity in SGC7901 cells and would be a promising chemotherapic agent for the treatment of gastric cancer.

Hsu FT, Liu YC, Liu TT, Hwang JJ
Curcumin Sensitizes Hepatocellular Carcinoma Cells to Radiation via Suppression of Radiation-Induced NF-κB Activity.
Biomed Res Int. 2015; 2015:363671 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
The effects and possible underlying mechanism of curcumin combined with radiation in human hepatocellular carcinoma (HCC) cells in vitro were evaluated. The effects of curcumin, radiation, and combination of both on cell viability, apoptosis, NF-κB activation, and expressions of NF-κB downstream effector proteins were investigated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), NF-κB reporter gene, mitochondrial membrane potential (MMP), electrophoretic mobility shift (EMSA), and Western blot assays in Huh7-NF-κB-luc2, Hep3B, and HepG2 cells. Effect of I kappa B alpha mutant (IκBαM) vector, a specific inhibitor of NF-κB activation, on radiation-induced loss of MMP was also evaluated. Results show that curcumin not only significantly enhances radiation-induced cytotoxicity and depletion of MMP but inhibits radiation-induced NF-κB activity and expressions of NF-κB downstream proteins in HCC cells. IκBαM vector also shows similar effects. In conclusion, we suggest that curcumin augments anticancer effects of radiation via the suppression of NF-κB activation.

Xia Y, Weng B, Wang Z, et al.
W346 inhibits cell growth, invasion, induces cycle arrest and potentiates apoptosis in human gastric cancer cells in vitro through the NF-κB signaling pathway.
Tumour Biol. 2016; 37(4):4791-801 [PubMed] Related Publications
The therapeutic agent selectively killing cancer cells is urgently needed for gastric cancer treatment. Curcumin has been investigated for its effect on the cancer treatment because of its significant therapeutic potential and safety profile. A synthetic unsymmetry mono-carbonyl compound termed W346 was developed from curcumin. In this study, we investigated the potential antineoplastic effect and mechanism of W346 against human gastric cancer cells. W346 suppressed the proliferation and invasion, blocked cell cycle arrest at G2/M phase, and increased apoptosis in gastric cancer cells, and it presented obviously improved anticancer activity than curcumin. Moreover, W346 effectively inhibited tumor necrosis factor (TNF-α)-induced NF-κB activation by suppressing IKK phosphorylation, inhibiting IκB-α degradation, and restraining the accumulation of NF-κB subunit p65 nuclear translocation. W346 also affected NF-κB-regulated downstream products involved in cycle arrest and apoptosis. In a word, W346 exhibited significantly improved anti-gastric cancer activity over curcumin by targeting NF-κB signaling pathway, and it is likely to be a promising starting point for the development of curcumin-based therapeutic agent.

Shi Z, Wu X, Ke Y, Wang L
Hint1 Up-Regulates IκBα by Targeting the β-TrCP Subunit of SCF E3 Ligase in Human Hepatocellular Carcinoma Cells.
Dig Dis Sci. 2016; 61(3):785-94 [PubMed] Related Publications
BACKGROUND AND AIM: There is increasing evidence that histidine triad nucleotide-binding protein 1 (HINT1) is a novel tumor suppressor. In the present study, we investigated the mechanism by which HINT1 promotes the stability of inhibitor of NF-κB α (IκBα) in the cytoplasm of hepatocellular carcinoma (HCC) cells, which was observed in our previous study (Wang et al. in Int J Cancer 124:1526-1534, 2009).
METHODS: We examined HINT1 and IκBα expression in HCC cell lines and determined the effect of HINT1 overexpression and knockdown on IκBα protein and mRNA expression in these cell lines. Then, ubiquitination assays were performed to investigate the effects of HINT1 expression plasmid transfection on IκBα ubiquitination. Next, the interaction between HINT1 and β-TrCP was investigated in immunoprecipitation and immunofluorescence assays.
RESULTS: Our data showed that increased HINT1 expression in HepG2 and SMMC7702 cells markedly increased IκBα protein levels, while decreased HINT1 expression markedly decreased them. Overexpression or knockdown of HINT1 did not alter the transcription of IκBα, but HINT1 inhibited proteasomal IκBα degradation and reduced its ubiquitination levels. This inhibition might occur because HINT1 is a component of the SCF(β-TrCP) E3 ligase, which is responsible for IκBα ubiquitination and degradation.
CONCLUSION: This study provides new evidence that HINT1 is a regulator of IκBα through SCF(β-TrCP) E3 ligase. These findings help to clarify the mechanism underlying the anticancer effects of HINT1.

Liu C, Zheng L, Wang H, et al.
The RCAN1 inhibits NF-κB and suppresses lymphoma growth in mice.
Cell Death Dis. 2015; 6:e1929 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Nuclear factor-κB (NF-κB) has a vital role in cell survival. Inhibition of NF-κB has been proven to be an efficient therapeutic pathway for various cancers. Activation of NF-κB is mainly through serine residues' phosphorylation of inhibitor of κBα (IκBα) by IKK complex. Phosphorylation at tyrosine 42 is an alternative pathway in regulation of IκBα and NF-κB signaling, though little is known about the underlying mechanism. Here we identified regulator of calcineurin 1 (RCAN1) as a novel endogenous inhibitor of NF-κB signaling pathway. RCAN1 can interact with IκBα and affect the phosphorylation of IκBα at tyrosine 42. Overexpression of RCAN1 by adenovirus reduced cell viability in lymphoma Raji cells and restrained the growth of lymphoma transplants in mice. We further found that N terminus 1-103aa of RCAN1 is sufficient to inhibit NF-κB and reduce cell viability of lymphoma cells. Our study implicated a novel therapeutic approach for lymphoma by RCAN1 through inhibition of NF-κB signaling.

Zhang M, Huang J, Tan X, et al.
Common Polymorphisms in the NFKBIA Gene and Cancer Susceptibility: A Meta-Analysis.
Med Sci Monit. 2015; 21:3186-96 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
BACKGROUND: NFKBIA encodes the inhibitors of nuclear factor-κB (NF-κB), which regulate the translation of the genes involved in the inflammatory and immune reactions. Polymorphisms (rs2233406, rs3138053, and rs696) of NFKBIA have been implicated in susceptibility to many cancer types.
MATERIAL AND METHODS: To evaluate the association between polymorphisms of NFKBIA and cancer susceptibility, a meta-analysis including a total of 7182 cancer cases and 10 057 controls from 28 case-control studies was performed. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.
RESULTS: Combined data demonstrated that rs3138053 polymorphism of NFKBIA was associated with cancer susceptibility in an allelic model (C vs. T: OR=10.754, 95%CI=4.175-27.697, Pheterogeneity=0.000), while the polymorphism of rs696 appeared to play a protective role in tumorigenesis (CC+CT vs. TT: OR=0.879, 95%CI=0.787-0.982, Pheterogeneity=0.107). When stratification analysis was performed by cancer type, an increased association of rs3138053 was recognized in hepatocarcinoma (C vs. T: OR=42.180, 95%CI=27.970-63.612, Pheterogeneity=0.007), while a decreased association of rs696 was identified in Hodgkin lymphoma (C vs. T: OR=0.792, 95%CI=0.656-0.956, Pheterogeneity=0.116; CC vs. TT: OR=0.658, 95%CI=0.448-0.965, Pheterogeneity=0.076; CC vs. CT+TT: OR=0.734, 95%CI=0.562-0.958, Pheterogeneity=0.347). By ethnicity, rs696 appears to be a protective candidate among Caucasians (CT vs. TT: OR=0.809, 95%CI=0.676-0.969, Pheterogeneity=0.459).
CONCLUSIONS: Our data demonstrated that the rs3138053 polymorphism of NFKBIA gene is a candidate for susceptibility to overall cancers, while rs696 plays a protective role.

Čokić VP, Mojsilović S, Jauković A, et al.
Gene expression profile of circulating CD34(+) cells and granulocytes in chronic myeloid leukemia.
Blood Cells Mol Dis. 2015; 55(4):373-81 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
PURPOSE: We compared the gene expression profile of peripheral blood CD34(+) cells and granulocytes in subjects with chronic myeloid leukemia (CML), with the accent on signaling pathways affected by BCR-ABL oncogene.
METHODS: The microarray analyses have been performed in circulating CD34(+) cells and granulocytes from peripheral blood of 7 subjects with CML and 7 healthy donors. All studied BCR-ABL positive CML patients were in chronic phase, with a mean value of 2012±SD of CD34(+)cells/μl in peripheral blood.
RESULTS: The gene expression profile was more prominent in CML CD34(+) cells (3553 genes) compared to granulocytes (2701 genes). The 41 and 39 genes were significantly upregulated in CML CD34(+) cells (HINT1, TXN, SERBP1) and granulocytes, respectively. BCR-ABL oncogene activated PI3K/AKT and MAPK signaling through significant upregulation of PTPN11, CDK4/6, and MYC and reduction of E2F1, KRAS, and NFKBIA gene expression in CD34(+) cells. Among genes linked to the inhibition of cellular proliferation by BCR-ABL inhibitor Imatinib, the FOS and STAT1 demonstrated significantly decreased expression in CML.
CONCLUSION: The presence of BCR-ABL fusion gene doubled the expression quantity of genes involved in the regulation of cell cycle, proliferation and apoptosis of CD34(+) cells. These results determined the modified genes in PI3K/AKT and MAPK signaling of CML subjects.

Mak P, Li J, Samanta S, Mercurio AM
ERβ regulation of NF-kB activation in prostate cancer is mediated by HIF-1.
Oncotarget. 2015; 6(37):40247-54 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
We examined the regulation of NF-κB in prostate cancer by estrogen receptor β (ERβ) based on the inverse correlation between p65 and ERβ expression that exists in prostate carcinomas and reports that ERβ can inhibit NF-κB activation, although the mechanism is not known. We demonstrate that ERβ functions as a gate-keeper for NF-κB p65 signaling by repressing its expression and nuclear translocation. ERβ regulation of NF-κB signaling is mediated by HIF-1. Loss of ERβ or hypoxia stabilizes HIF-1α, which we found to be a direct driver of IKKβ transcription through a hypoxia response element present in the promoter of the IKKβ gene. The increase of IKKβ expression in ERβ-ablated cells correlates with an increase in phospho-IκBα and concomitant p65 nuclear translocation. An inverse correlation between the expression of ERβ and IKKβ/p65 was also observed in the prostates of ERβ knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ERβ prevents NF-κB activation and raise the exciting possibility that loss of ERβ expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer.

Yao S, Hu M, Hao T, et al.
MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-κB signaling.
Nucleic Acids Res. 2015; 43(19):9362-78 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Co-infection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of aggressive AIDS-related Kaposi's sarcoma (AIDS-KS) characterized by abnormal angiogenesis. The impact of HIV-1 and KSHV interaction on the pathogenesis and extensive angiogenesis of AIDS-KS remains unclear. Here, we explored the synergistic effect of HIV-1 Tat and KSHV oncogene Orf-K1 on angiogenesis. Our results showed that soluble Tat or ectopic expression of Tat enhanced K1-induced cell proliferation, microtubule formation and angiogenesis in chorioallantoic membrane and nude mice models. Mechanistic studies revealed that Tat promoted K1-induced angiogenesis by enhancing NF-κB signaling. Mechanistically, we showed that Tat synergized with K1 to induce the expression of miR-891a-5p, which directly targeted IκBα 3' untranslated region, leading to NF-κB activation. Consequently, inhibition of miR-891a-5p increased IκBα level, prevented nuclear translocation of NF-κB p65 and ultimately suppressed the synergistic effect of Tat- and K1-induced angiogenesis. Our results illustrate that, by targeting IκBα to activate the NF-κB pathway, miR-891a-5p mediates Tat and K1 synergistic induction of angiogenesis. Therefore, the miR-891a-5p/NF-κB pathway is important in the pathogenesis of AIDS-KS, which could be an attractive therapeutic target for AIDS-KS.

Gupta A, Kumar R, Sahu V, et al.
NFκB-p50 as a blood based protein marker for early diagnosis and prognosis of head and neck squamous cell carcinoma.
Biochem Biophys Res Commun. 2015; 467(2):248-53 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) is the major health concern in Indian population. Despite of advanced treatment the mortality rate for this disease has not been improved very much. Current research focused on development of protein marker for the diagnosis and prognosis of HNSCC. The case control study was performed with 125 HNSCC patients and 104 control cases. The level of p50 and IκBα proteins in serum were evaluated at pre and post therapy by label free real time surface plasmon resonance (SPR) and western blot analysis. The serum p50 concentration were significantly (P < 0.0001) higher at the time of diagnosis i.e. pre therapy (Mean ± SD = 27.06 ± 4.88 ng/μl) as compared to controls (Mean ± SD = 16.96 ± 4.04 ng/μl) while it decline at post therapy (Mean ± SD = 21.01 ± 4.98 ng/μl). Similarly, the concentration of IκBα protein in serum were slightly higher at pre therapy (Mean ± SD = 8.33 ± 1.85 ng/μl) as compared to controls (Mean ± SD = 7.27 ± 1.84 ng/μl) and declined at post therapy (Mean ± SD = 7.09 ± 1.24 ng/μl). The level of p50 was also high at the early stage of the disease. The specificity and sensitivity of p50 proteins obtained from ROC analysis revealed the potentiality to be diagnostic protein marker for HNSCC for its accuracy in the study cohort.

Prabhu L, Mundade R, Wang B, et al.
Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer.
Oncotarget. 2015; 6(30):29396-412 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Y-box binding protein 1 [YBX1] is a multifunctional protein known to facilitate many of the hallmarks of cancer. Elevated levels of YBX1 protein are highly correlated with cancer progression, making it an excellent marker in cancer. The connection between YBX1 and the important nuclear factor κB [NF-κB] has never been reported. Here, we show that overexpression of wild type YBX1 [WT-YBX1] activates NF-κB, suggesting that YBX1 is a potential NF-κB activator. Furthermore, using mass spectrometry analysis we identified novel phosphorylation of serine 165 [S165] on YBX1. Overexpression of the S165A-YBX1 mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB activating ability as compared with that of WT-YBX1, confirming that S165 phosphorylation is critical for the activation of NF-κB by YBX1. We also show that expression of the S165A-YBX1 mutant dramatically decreased the expression of NF-κB-inducible genes, reduced cell growth, and compromised tumorigenic ability as compared with WT-YBX1. Taken together, we provide the first evidence that YBX1 functions as a tumor promoter via NF-κB activation, and phosphorylation of S165 of YBX1 is critical for this function. Therefore, our important discovery may lead to blocking S165 phosphorylation as a potential therapeutic strategy to treat colon cancer.

Crivellaro S, Panuzzo C, Carrà G, et al.
Non genomic loss of function of tumor suppressors in CML: BCR-ABL promotes IκBα mediated p53 nuclear exclusion.
Oncotarget. 2015; 6(28):25217-25 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Tumor suppressor function can be modulated by subtle variation of expression levels, proper cellular compartmentalization and post-translational modifications, such as phosphorylation, acetylation and sumoylation. The non-genomic loss of function of tumor suppressors offers a challenging therapeutic opportunity. The reactivation of a tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. The identification of mechanisms that affect tumor suppressor functions is therefore essential. In this work, we show that BCR-ABL promotes the accumulation of the NFKBIA gene product, IκBα, in the cytosol through physical interaction and stabilization of the protein. Furthermore, BCR-ABL/IκBα complex acts as a scaffold protein favoring p53 nuclear exclusion. We therefore identify a novel BCR-ABL/IκBα/p53 network, whereby BCR-ABL functionally inactivates a key tumor suppressor.

Huang Z, Zhong Z, Zhang L, et al.
Down-regulation of HMGB1 expression by shRNA constructs inhibits the bioactivity of urothelial carcinoma cell lines via the NF-κB pathway.
Sci Rep. 2015; 5:12807 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
The high mobility group box 1 (HMGB1), which is a highly conserved and evolutionarily non-histone nuclear protein, has been shown to associate with a variety of biological important processes, such as transcription, DNA repair, differentiation, and extracellular signalling. High HMGB1 expression has been reported in many cancers, such as prostate, kidney, ovarian, and gastric cancer. However, there have been few studies of the function of HMGB1 in the malignant biological behaviour of bladder urothelial carcinoma (BUC), and the potential mechanism of HMGB1 in the pathogenesis of BUC remains unclear. Thus, in this study, we constructed plasmid vectors that are capable of synthesizing specific shRNAs targeting HMGB1 and transfected them into BUC cells to persistently suppress the endogenous gene expression of HMGB1. The expression of HMGB1, the bioactivity of BUC cells, including proliferation, apoptosis, cell cycle distribution, migration and invasion, and the effects of HMGB1 knockdown on downstream signalling pathways were investigated. Our data suggest that HMGB1 promotes the malignant biological behaviour of BUC, and that this effect may be partially mediated by the NF-κB signalling pathway. HMGB1 may serve as a potential therapeutic target for BUC in the future.

Ku JM, Kim SR, Hong SH, et al.
Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells.
Mol Cell Biochem. 2015; 409(1-2):33-43 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Breast cancer is the most common cancer for women and is a major cause of mortality in women. Doxorubicin is a generally used chemotherapy drug for breast cancer. However, multidrug resistance of breast cancer interferes with the chemotherapy. We examined whether cucurbitacin D affects doxorubicin resistance of MCF7/ADR breast cancer cells. Cell viability was measured by MTT assay. Levels of p-STAT3, p-NF-κB, IκB, and caspases were measured by Western blot analysis. Nuclear staining of Stat3 and NF-κB was measured by immunocytochemistry. STAT3 and NF-κB transcriptional activity was detected by STAT3 and NF-κB luciferase reporter gene assays. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by Annexin V-FITC/propidium iodide assay. More than 90% of MCF7/ADR cells lived upon treatment with doxorubicin for 24 h. However, upon treatment with cucurbitacin D, cell death was more than 60%. Co-administration of cucurbitacin D and doxorubicin induced apoptosis, and G2/M cell cycle arrest, and inhibited upregulated Stat3 by doxorubicin on MCF7/ADR cells. Additionally, cucurbitacin D led to an increase in the IκBα level in the cytosol and a decrease in the p-NF-κB level in the nucleus. Finally, cucurbitacin D inhibited translocation of Stat3 and NF-κB and decreased transcriptional activity in the nucleus. Cucurbitacin D decreases cell proliferation and induces apoptosis by inhibiting Stat3 and NF-κB signaling in doxorubicin-resistant breast cancer cells. Cucurbitacin D could be used as a useful compound to treat adriamycin-resistant patients.

Wang Z, Zhang L, Ni Z, et al.
Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity.
Tumour Biol. 2015; 36(12):9499-510 [PubMed] Related Publications
Resveratrol, a natural polyphenolic compound found in foods and beverages, has attracted increasing attention in recent years because of its potent chemopreventive and anti-tumor effects. In this study, the effects of resveratrol on the expression of P-glycoprotein/multi-drug resistance protein 1 (P-gp/MDR1), and the underlying molecular mechanisms, were investigated in oxaliplatin (L-OHP)-resistant colorectal cancer cells (HCT116/L-OHP). Resveratrol downregulated MDR1 protein and mRNA expression levels and reduced MDR1 promoter activity. It also enhanced the intracellular accumulation of rhodamine 123, suggesting that resveratrol can reverse multi-drug resistance by downregulating MDR1 expression and reducing drug efflux. Resveratrol treatment also reduced nuclear factor-κB (NF-κB) activity, reduced phosphorylation levels of IκBα, and reduced nuclear translocation of the NF-κB subunit p65. Moreover, downregulation of MDR1 expression and promoter activity was mediated by resveratrol-induced AMP-activated protein kinase (AMPK) phosphorylation. The inhibitory effects of resveratrol on MDR1 expression and cAMP-responsive element-binding protein (CREB) phosphorylation were reversed by AMPKα siRNA transfection. We found that the transcriptional activity of cAMP-responsive element (CRE) was inhibited by resveratrol. These results demonstrated that the inhibitory effects of resveratrol on MDR1 expression in HCT116/L-OHP cells were closely associated with the inhibition of NF-κB signaling and CREB activation in an AMPK-dependent manner.

Widel M, Lalik A, Krzywon A, et al.
The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status.
Mutat Res. 2015; 778:61-70 [PubMed] Related Publications
Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0-8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at lower doses whereas wild type cells only at higher doses. Secretion of IL-8 by TP53-/- control cells was many times lower than that by TP53+/+ but increased significantly after irradiation. Transcription of the NFκBIA was induced in irradiated TP53+/+ mainly, but in bystanders a higher level was observed in TP53-/- cells, suggesting that TP53 is required for induction of NFκB pathway after irradiation but another mechanism of activation must operate in bystander cells.

Han X, Zhang JJ, Yao N, et al.
Polymorphisms in NFKB1 and NFKBIA Genes Modulate the Risk of Developing Prostate Cancer among Han Chinese.
Med Sci Monit. 2015; 21:1707-15 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
BACKGROUND: Nuclear factor kappa B (NF-κB) pathway proteins play an important role in modulating inflammation and other carcinogenic processes. Polymorphisms within NF-κB pathway genes may influence cancer risk. This study aimed to examine the association between NFKB19-4 ATTG ins→del, NFKBIA 3' UTR A→G, -826CT and -881AG polymorphisms and prostate cancer risk among Chinese.
MATERIAL AND METHODS: The polymorphisms were genotyped via PCR-RFLP technique on 936 prostate cancer patients and 936 population-based healthy controls. Logistic regression model was used to measure the risk association present.
RESULTS: With the exception of NFKBIA 3' UTR polymorphism, the heterozygous and mutant genotypes of the other polymorphisms were significantly associated with prostate cancer risk. For NFKB1 polymorphism, a decreased risk was observed, with adjusted OR: 0.69; 95% CI: 0.44, 0.98; P=0.01 (heterozygous) and adjusted OR: 0.60; 95% CI: 0.37, 0.91; P=0.02 (mutant). NFKBIA -826CT and -881AG polymorphisms were in complete linkage disequilibrium and shared the same risk association, with adjusted OR: 1.34; 95% CI: 1.09, 1.62; P=0.02 (heterozygous) and adjusted OR: 2.83; 95% CI: 1.79, 4.50; P=0.01 (mutants). Interestingly, the impact of the NFKB1 polymorphism was not present in nonsmokers and younger (<60 years) subjects (P<0.05).
CONCLUSIONS: In conclusion, polymorphisms in NFKB1 and NFKBIA genes may modulate the risk of developing prostate cancer among Chinese.

Camargo RG, Riccardi DM, Ribeiro HQ, et al.
NF-κBp65 and Expression of Its Pro-Inflammatory Target Genes Are Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients.
Nutrients. 2015; 7(6):4465-79 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.

Junk S, Cario G, Wittner N, et al.
Bortezomib Treatment can Overcome Glucocorticoid Resistance in Childhood B-cell Precursor Acute Lymphoblastic Leukemia Cell Lines.
Klin Padiatr. 2015; 227(3):123-30 [PubMed] Related Publications
BACKGROUND: The response to initial glucocorticoid (gc) treatment is a reliable stratification factor in childhood acute lymphoblastic leukemia (ALL) and may predict the response to multi-agent chemotherapy. In a former study we detected that the valosin-containing protein (VCP, cdc48), a member of the ubiquitin proteasome degradation system (UPS), is altered in gc-resistant leukemic cells suggesting that the associated pathways might be involved in chemotherapy resistance in childhood ALL.
METHODS: Human B-cell precursor leukemia cell lines, gc-resistant MHH-cALL-2 and gc-sensitive MHH-cALL-3, were treated with prednisolone and various concentrations of bortezomib. Viability and apoptosis rates were determined.
RESULTS: Both cell lines showed a dose-dependent increase in caspase activity after bortezomib single treatment. The gc-sensitive cells showed an additive effect after combined treatment with prednisolone and bortezomib. In contrast, both cell lines showed a reduced viability and enhanced propidium iodide positivity after combined treatment as determined by flow cytometry. Western blot analyses of poly-(ADP-ribose) polymerase 1 (PARP-1) suggested that combined treatment promote necrotic cleavage of PARP-1 in gc-resistant cells. Furthermore, after prednisolone treatment the UPS associated proteins VCP and NFκB-inhibitor IκBα were differentially modulated in gc-resistant cells.
CONCLUSIONS: The proteasome inhibitor bortezomib seems to sensitize gc-resistant childhood ALL cells for prednisolone-induced cell death.

Ch'ng WC, Abd-Aziz N, Ong MH, et al.
Human renal carcinoma cells respond to Newcastle disease virus infection through activation of the p38 MAPK/NF-κB/IκBα pathway.
Cell Oncol (Dordr). 2015; 38(4):279-88 [PubMed] Related Publications
PURPOSE: Newcastle disease virus (NDV) is an oncolytic virus that is known to have a higher preference to cancer cells than to normal cells. It has been proposed that this higher preference may be due to defects in the interferon (IFN) responses of cancer cells. The exact mechanism underlying this process, however, remains to be resolved. In the present study, we examined the antiviral response towards NDV infection of clear cell renal cell carcinoma (ccRCC) cells. ccRCC is associated with mutations of the von Hippel-Lindau tumor suppressor gene VHL, whose protein product is important for eliciting cellular responses to changes in oxygen levels. The most common first line treatment strategy of ccRCC includes IFN. Unfortunately, most ccRCC cases are diagnosed at a late stage and often are resistant to IFN-based therapies. Alternative treatment approaches, including virotherapy using oncolytic viruses, are currently being investigated. The present study was designed to investigate the mechanistic pathways underlying the response of ccRCC cells to oncolytic NDV infection.
METHODS AND RESULTS: We found that NDV induces activation of NF-κB in ccRCC cells by inducing phosphorylation and subsequent degradation of IκBα. IκBα was found to be phosphorylated as early as 1 hour post-infection and to result in rapid NF-κB nuclear translocation and activation. Importantly, p38 MAPK phosphorylation was found to occur upstream of the NDV-induced NF-κB activation. Restoration of VHL in ccRCC cells did not result in a reduction of this phosphorylation. A similar phenomenon was also observed in several other cancer-derived cell lines.
CONCLUSION: Our data provide evidence for involvement of the p38 MAPK/NF-κB/IκBα pathway in NDV infection and subsequent induction of apoptosis in ccRCC cells.

Pallavi S, Anoop K, Showket H, et al.
NFKB1/NFKBIa polymorphisms are associated with the progression of cervical carcinoma in HPV-infected postmenopausal women from rural area.
Tumour Biol. 2015; 36(8):6265-76 [PubMed] Related Publications
Human papillomavirus (HPV) is considered as the major etiological agent for development of cervical cancer but alone is not sufficient enough. So, other environmental factors and host genetic background may play an important role in the development of cervical cancer. HPV carries a minimal amount of structural and regulatory proteins so it is apparently dependent on its host for survival. NF-κB/IkB system plays an important regulatory role in the apoptotic pathway. In the present study, a total of 575 consecutive subjects including 285 cases (45 cervical pre-cancerous and 240 invasive cervical carcinoma) and 290 age- and ethnicity-matched controls recruited from Lok Nayak Jai Prakash Hospital and Safdarjung Hospital, New Delhi between July 2009 to July 2013 were genotyped for NFKB1 -94 insertion/deletion (rs28362491) and NFKBIa 3'-UTR2758A > G (rs696) polymorphism by PCR-RFLP followed by sequencing. We observed a positive association of NFKB1 -94 insertion/insertion (II) and NFKBIa 3'-UTR 2758 GG genotypes with the progression of cervical carcinoma. Cervical cancer patients were found more pronounce to be a carrier of II + GG genotype of both the SNPs. We also noticed that HPV-infected postmenopausal women having higher parity along with the history of tobacco consumption and who carries insertion allele of NFKB1 -94 polymorphism in association of GG genotype of NFKBIa 3'-UTR polymorphism, were more susceptible to develop cervical carcinoma. II + GG genotype together were found to have direct proportionality with the aggressiveness of cervical carcinoma. In conclusion, alteration in the gene map of NFKB1/NFKBIa helps in the progression of cervical cancer accompanied by HPV infection in postmenopausal women from rural residential setup who had higher parity along with history of tobacco consumption.

Yang HJ, Wang M, Wang L, et al.
NF-κB regulates caspase-4 expression and sensitizes neuroblastoma cells to Fas-induced apoptosis.
PLoS One. 2015; 10(2):e0117953 [PubMed] Article available free on PMC after 06/04/2017 Related Publications
Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-κB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-κB activation in Fas killing and the effect of NF-κB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-κB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-κB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IκBα (DN-IκBα) or an IκB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-κB signaling, we found that DN-IκBα only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-κB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-κB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-κB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-κB pro-apoptotic pathway in neuroblastoma cells.

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