Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IKBKE (cancer-related)
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.
Breast cancer (BC) is the second leading cause of death among women in the US, and its subtype triple-negative BC (TNBC) is the most aggressive BC with poor prognosis. In the current study, we investigated the anticancer effects of the natural product plumbagin (PL) on racially different TNBC cells. The PL effects were examined in two TNBC cell lines: MDA-MB-231 (MM-231) and MDA-MB-468 (MM-468), representing Caucasian Americans and African Americans, respectively. The results obtained indicate that PL inhibited cell viability and cell proliferation and induced apoptosis in both cell lines. Notably, MM-468 cells were 5-fold more sensitive to PL than MM-231 cells were. Testing PL and Taxol® showed the superiority of PL over Taxol® as an antiproliferative agent in MM-468 cells. PL treatment resulted in an approximately 20-fold increase in caspase-3 activity with 3 μM PL in MM-468 cells compared with an approximately 3-fold activity increase in MM-231 cells with 8 μM PL. Moreover, the results indicate a higher sensitivity to PL in MM-468 cells than in MM-231 cells. The results also show that PL downregulated CCL2 cytokine expression in MM-468 cells by 30% compared to a 90% downregulation in MM-231 cells. The ELISA results confirmed the array data (35% vs. 75% downregulation in MM-468 and MM-231 cells, respectively). Moreover, PL significantly downregulated IL-6 and GM-CSF in the MM-231 cells. Indeed, PL repressed many NF-қB-regulated genes involved in the regulation of apoptosis, proliferation, invasion, and metastasis. The compound significantly downregulated the same genes (BIRC3, CCL2, TLR2, and TNF) in both types of cells. However, PL impacted five more genes in MM-231 cells, including BCL2A1, ICAM1, IKBKE, IL1β, and LTA. In conclusion, the data obtained in this study indicate that the quinone compound PL could be a novel cancer treatment for TNBC in African American women.
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC.
METHODS: Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition.
RESULTS: This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins.
CONCLUSIONS: This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.
The inhibitor of kappa B kinase epsilon is overexpressed in glioma and plays antiapoptotic role via activating nuclear factor-kappa B. microRNA-98 can suppress glioma, modulate the activities of nuclear factor-kappa B, and bind to the 3'-untranslated region of inhibitor of kappa B kinase epsilon messenger RNA. This study was aimed to investigate the modulation of inhibitor of kappa B kinase epsilon/nuclear factor-kappa B by microRNA-98 in glioma. The results indicated that microRNA-98 was downregulated in glioma cell lines and human glioma tissues. Overexpression of microRNA-98 in U87MG and T98G glioma cells significantly increased the apoptosis induced by ultraviolet irradiation and suppressed nuclear factor-kappa B luciferase activity, nuclear factor-kappa B p50 subunit expression, and B-cell lymphoma-2 (Bcl-2) expression in glioma cells. Silencing inhibitor of kappa B kinase epsilon decreased the expression of nuclear factor-kappa B p50 subunit and the luciferase activity of nuclear factor-kappa B, while the nuclear factor-kappa B activity could be significantly retrieved when inhibitor of kappa B kinase epsilon was expressed in microRNA-98-transfected cells. These findings indicated that microRNA-98 could promote apoptosis of glioma cells via inhibiting inhibitor of kappa B kinase epsilon/nuclear factor-kappa B signaling and presented a novel regulatory pathway of microRNA-98 by direct suppression of inhibitor of kappa B kinase epsilon/nuclear factor-kappa B expression in glioma cells.
Glioblastoma multiforme (GBM) is the most prevalent form of malignant brain tumor. Amlexanox, a novel compound, has been shown to have anti-cancer potential. In this study, the anti-tumoral effects and the underlying mechanisms of amlexanox were investigated. Amlexanox significantly suppressed proliferation and invasion and induced apoptosis in glioblastoma cells. Furthermore, we found that amlexanox altered the protein expression of the Hippo pathway by downregulating IKBKE. Our data indicates that IKBKE directly targets LATS1/2 and induces degradation of LATS1/2, thereby inhibiting the activity of the Hippo pathway. In vivo results further confirmed the tumor inhibitory effect of amlexanox via the downregulation of IKBKE, and amlexanox induced no apparent toxicity. Collectively, our studies suggest that amlexanox is a promising therapeutic agent for the treatment of GBM.
Zhang Z, Lu J, Guo G, et al.IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i.
Tumour Biol. 2017; 39(7):1010428317705575 [PubMed
] Related Publications
Recently, we have demonstrated that IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is overexpressed in human glioblastoma and that inhibition of IKBKE remarkably suppresses the proliferative and invasive behaviour of glioblastoma cells. However, the specific pathogenic molecular mechanism remains to be elucidated. In this study, we verified that IKBKE promotes YAP1 expression via posttranslational modification and accelerates YAP1 translocation to the nucleus for the development of glioblastoma. We then determined that YAP1 negatively regulates miR-let-7b/i by overexpressing and silencing YAP1 expression. In addition, miR-let-7b/i feedback decreases the expression of IKBKE and YAP1 and suppresses the transportation of YAP1 located in the nucleus. Therefore, the regulatory feedback circuit of IKBKE↑→YAP1↑→miR-let-7b/i↓→IKBKE↑ dictates glioblastoma progression. Thus, we propose that blocking the circuit may be a new therapeutic strategy for the treatment of glioblastoma.
IKBKE is increased in several types of cancers and is associated with tumour malignancy. In this study, we confirmed that IKBKE promoted glioma proliferation, migration and invasion in vitro. Then, we further discovered that IKBKE increased Yes-associated protein 1 (YAP1) and TEA domain family member 2 (TEAD2), two important Hippo pathway downstream factors, to induce an epithelial-mesenchymal transition (EMT), thus contributing to tumour invasion and metastasis. We also testified that YAP1 and TEAD2 promoted epithelial-mesenchymal transition (EMT) in malignant glioma. Furthermore, we constructed nude mouse subcutaneous and intracranial models to verify that IKBKE could attenuate U87-MG tumourigenicity in vivo. Collectively, our results suggest that IKBKE plays a pivotal role in regulating cell proliferation, invasion and epithelial-mesenchymal transition of malignant glioma cells in vitro and in vivo by impacting on the Hippo pathway. Therefore, targeting IKBKE may become a new strategy to treat malignant glioma.
Péant B, Gilbert S, Le Page C, et al.IκB-Kinase-epsilon (IKKε) over-expression promotes the growth of prostate cancer through the C/EBP-β dependent activation of IL-6 gene expression.
Oncotarget. 2017; 8(9):14487-14501 [PubMed
] Free Access to Full Article Related Publications
The inflammatory cytokine IL-6 has been shown to induce the nuclear translocation of androgen receptors in prostate cancer cells and to activate the androgen receptors in a ligand-independent manner, suggesting it may contribute to the development of a castrate-resistant phenotype. Elevated IL-6 serum levels have also been associated with metastasis-related morbidity in prostate cancer patients. We have previously established that over-expression of I-kappa-B-kinase-epsilon (IKKε also named IKKi or IκBKε) in hormone-sensitive prostate cancer cell lines induces IL-6 secretion. We have also reported that prostate cancer cell lines lacking androgen receptor expression exhibit high constitutive IKKε expression and IL-6 secretion. In the present study, we validated the impact of IKKε depletion on the in vitro proliferation of castrate-resistant prostate cancer cells, and characterized how IKKε depletion affects tumor growth and IL-6 tumor secretion in vivo through a mouse xenograft-based approach. We observed a significant growth delay in IKKε-silenced PC-3 cells injected in SCID mice fed with a doxycycline-supplemented diet in comparison with mice fed with a normal diet. We also found a decrease in IL-6 secretion levels that strongly correlated with tumor growth inhibition. Finally, using constructs with various IL-6-mutated promoters, we demonstrated that IKKε over-expression induces a NF-κB-independent stimulation of the IL-6 gene promoter through the activation and nuclear accumulation of the transcription factor C/EBP-β. Our study demonstrates the pro-proliferative role of the oncogene IKKε in castrate-resistant prostate cancer cell lines, involving the phosphorylation and nuclear translocation of C/EBP-β that initiates IL-6 gene expression.
Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.
Zhu M, Wang M, Yang F, et al.miR-155-5p inhibition promotes the transition of bone marrow mesenchymal stem cells to gastric cancer tissue derived MSC-like cells via NF-κB p65 activation.
Oncotarget. 2016; 7(13):16567-80 [PubMed
] Free Access to Full Article Related Publications
Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-κB p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKKε) were identified as targets of miR-155-5p and important for miRNA inhibitor activating NF-κB p65 in the transition. Inactivation of NF-κB by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-κB p65 and phospho-NF-κB p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-κB p65 protein was increased and activated. NF-κB inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-κB p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy.
Li W, Chen Y, Zhang J, et al.IKBKE Upregulation is Positively Associated with Squamous Cell Carcinoma of the Lung In Vivo and Malignant Transformation of Human Bronchial Epithelial Cells In Vitro.
Med Sci Monit. 2015; 21:1577-86 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The IκB kinase inhibitor of κB kinase epsilon (IKBKE) is overexpressed in several human cancers. Although IKBKE plays an important role in smoking-induced non-small cell lung cancer carcinogenesis, its role in squamous cell carcinoma of the lung (SCCL) remains unclear.
MATERIAL AND METHODS: IKBKE protein expression was assessed by immunohistochemistry in 288 paraffinized SCCL specimens (with adjacent squamous dysplastic and normal tissue). IKBKE mRNA expression was assessed by reverse transcription PCR in 66 fresh SCCL specimens (with adjacent squamous dysplastic and normal tissue). Separately, immortalized human bronchial epithelial cells were cultured in 7 groups: untreated control, ethanol-treated, and cigarette smoke condensate (CSC)-exposed for 10, 20, 30, 40, and 50 generations (P10, P20, P30, P40, and P50, respectively). Malignant transformation was assessed by serum resistance and colony formation assays. IKBKE protein and mRNA expression were detected by Western blotting and reverse transcription PCR, respectively.
RESULTS: IKBKE protein expression showed a significant upward trend from normal bronchial epithelium to squamous cell dysplasia to SCCL. IKBKE protein expression in SCCL was significantly associated with smoking status, smoking index, degree of differentiation, and clinical stage. Current and former smokers displayed significantly higher IKBKE protein and mRNA expression than non-smokers. IKBKE protein and mRNA expression displayed a significant upward trend with the smoking index. P30, P40, and P50 CSC-exposed cells displayed malignant transformation with increasing IKBKE mRNA and protein expression from P20 through P50.
CONCLUSIONS: IKBKE upregulation is positively associated with SCCL and smoking indices as well as CSC-induced malignant transformation of human bronchial epithelial cells.
Tang D, Sun B, Yu H, et al.Tumor-suppressing effect of miR-4458 on human hepatocellular carcinoma.
Cell Physiol Biochem. 2015; 35(5):1797-807 [PubMed
] Related Publications
BACKGROUND: Besides multiple genetic and epigenetic changes of protein coding genes in hepatocellular carcinoma (HCC), growing evidence indicate that deregulation of miRNAs contribute to HCC development by influencing cell growth, apoptosis, migration, or invasion. IKBKE is amplified and over-expressed in a large percentage of human breast tumors and identified as an oncogene of human breast tumor. Microarray analysis showed that miR-4458 was down-regulated in HCC tissues.
METHODS: The level of miR-4458 was up-regulated by miR-4458 mimics transfection, or down-regulated by miR-4458 ASO transfection. Cell proliferation was assayed by MTT analysis. MiRNAs and mRNA expression were assayed by qRT-PCR. These potential targeted genes of miR-4458 were predicted by bioinformatic algorithms. Dual luciferase reporter assay system was used to analyze the interaction between miR-4458 and IKBKE. IKBKE protein level was assayed by Western blot. The role of miR-4458 or IKBKE in the survival of HCC patients were revealed by Kaplan-Meier plot of overall survival.
RESULTS: Lower miR-4458 expression level or higher IKBKE level in HCC tissues correlated with worse prognosis of HCC patients. Overexpression of miR-4458 inhibited the HCC cells growth and vice versa. MiR-4458 played its role via targeting 3'UTR of IKBKE.
CONCLUSIONS: MiR-4458 or IKBKE may be potential predictors of HCC prognosis. Restoration of miR-4458 or inhibition of IKBKE could be a prospective therapeutic approach for HCC.
Tian Y, Hao S, Ye M, et al.MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly.
Biochem Biophys Res Commun. 2015; 458(2):307-12 [PubMed
] Related Publications
We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin.
Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.
Ku X, Heinzlmeir S, Liu X, et al.A new chemical probe for quantitative proteomic profiling of fibroblast growth factor receptor and its inhibitors.
J Proteomics. 2014; 96:44-55 [PubMed
] Related Publications
UNLABELLED: Recent advances in mass spectrometry-based chemical proteomics allow unbiased analysis of drug-target interactions under close to physiological conditions. In this study, we designed and synthesized two small molecule probes targeting fibroblast growth factor receptors (FGFRs) and applied them to evaluate the selectivity profiles of the FGFR inhibitors Dovitinib and Orantinib. Probe F2 was capable of enriching all members of the FGF receptor family as well as other kinases involved in cancer such as KDR, FLT4 and RET from lysates of cancer cells or human placenta tissue. In combination with the established Kinobeads™ approach, probe F2 facilitated the identification of the target spectrum of the two inhibitors confirming many of the previously identified (off-) targets such as AURKA, FLT4-VEGFR3, IKBKE and PDGFRβ. The newly synthesized probe enlarges the arsenal of chemical proteomic tools for the expression profiling of kinases and selectivity profiling of their inhibitors. It will also be useful in applications aiming at a better understanding of a drug's cellular mechanisms of action as well as highlighting potential beneficial or adverse side effects.
BIOLOGICAL SIGNIFICANCE: The synthesis of a new chemical affinity probe targeting FGF-receptors and many other kinases improved the general scope of drug selectivity profiling by chemical proteomics. The application of the developed chemical tool identified most of the known targets for the advanced clinical kinase inhibitors Dovitinib and Orantinib thus exemplify the practical utility of the developed probe and the results obtained shed further light on how these drugs exert their anti-cancer activity in cells. More generally speaking, the significance of the work is that the molecular tools presented here extend the application scope of kinobeads based kinase profiling to FGFR/VEGFR/PDGFR families, which thus may be generically employed for selectivity profiling of kinase inhibitors using chemical proteomics. The overall aim of such studies is to improve our understanding of how target as well as off-target profiles can be used to assess or predict the therapeutic efficacy of a drug.
Elton TS, Selemon H, Elton SM, Parinandi NLRegulation of the MIR155 host gene in physiological and pathological processes.
Gene. 2013; 532(1):1-12 [PubMed
] Related Publications
MicroRNAs (miRNAs), a family of small nonprotein-coding RNAs, play a critical role in posttranscriptional gene regulation by acting as adaptors for the miRNA-induced silencing complex to inhibit gene expression by targeting mRNAs for translational repression and/or cleavage. miR-155-5p and miR-155-3p are processed from the B-cell Integration Cluster (BIC) gene (now designated, MIR155 host gene or MIR155HG). MiR-155-5p is highly expressed in both activated B- and T-cells and in monocytes/macrophages. MiR-155-5p is one of the best characterized miRNAs and recent data indicate that miR-155-5p plays a critical role in various physiological and pathological processes such as hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular disease, and Down syndrome. In this review we summarize the mechanisms by which MIR155HG expression can be regulated. Given that the pathologies mediated by miR-155-5p result from the over-expression of this miRNA it may be possible to therapeutically attenuate miR-155-5p levels in the treatment of several pathological processes.
Serine/threonine kinase IKBKE is a newly identified oncogene; however, its regulation remains elusive. Here, we provide evidence that IKBKE is a downstream target of signal transducer and activator of transcription 3 (STAT3) and that tobacco components induce IKBKE expression through STAT3. Ectopic expression of constitutively active STAT3 increased IKBKE mRNA and protein levels, whereas inhibition of STAT3 reduced IKBKE expression. Furthermore, expression levels of IKBKE are significantly associated with STAT3 activation and tobacco use history in non-small cell lung cancer (NSCLC) patients examined. In addition, we show induction of IKBKE by two components of cigarette smoke, nicotine and nicotine-derived nitrosamine ketone (NNK). Upon exposure to nicotine or NNK, cells express high levels of IKBKE protein and mRNA, which are largely abrogated by inhibition of STAT3. Characterization of the IKBKE promoter revealed two STAT3-response elements. The IKBKE promoter directly bound to STAT3 and responded to nicotine and NNK stimulation. Notably, enforcing expression of IKBKE induces chemoresistance, whereas knockdown of IKBKE not only sensitizes NSCLC cells to chemotherapy but also abrogates STAT3- and nicotine-induced cell survival. These data indicate for the first time that IKBKE is a direct target of STAT3 and is induced by tobacco carcinogens through STAT3 pathway. In addition, our study also suggests that IKBKE is an important therapeutic target and could have a pivotal role in tobacco-associated lung carcinogenesis.
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors.
There are 516 known kinases in the human genome. Because of their important role maintaining proper cellular function, they are often misregulated during tumorigenesis and associated with clinical outcomes in cancer patients, including clear cell renal cell carcinoma (ccRCC). However, less is known about the global expression status of these genes in renal cell carcinoma and their association with clinical outcomes. We performed a systematic analysis of gene expression for 503 kinases in 93 tumor samples and adjacent normal tissues. Expression patterns for 41 kinases were able to clearly differentiate tumor and normal samples. Expression of I-kappa-B kinase epsilon (IKBKE) was associated with a 5.3-fold increased risk of dying [95% confidence interval (CI): 1.93-14.59, P-value: 0.0012]. Individuals with high IKBKE expression were at a significantly increased risk of death (hazard ratio: 3.34, 95% CI: 1.07-10.40, P-value: 0.038) resulting in a significantly reduced overall survival time compared with those with low IKBKE tumor expression (P-value: 0.049). These results for IKBKE were validated in a replication population consisting of 237 ccRCC patients (P-value: 0.0021). Furthermore, IKBKE was observed to be higher expressed in tumors compared with adjacent normal tissues (P-value < 10(-7)). IKBKE is a member of the nuclear factor-kappaB (NF-κB) signaling pathway and interestingly, gene expression patterns for other members of the NF-κB pathway were not associated with survival, suggesting that IKBKE gene expression may be an independent marker of variation in overall survival. Overall, these results support a novel role for IKBKE expression in modulating overall survival in ccRCC patients.
Guo JP, Coppola D, Cheng JQIKBKE protein activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and the pleckstrin homology domain to sustain malignant transformation.
J Biol Chem. 2011; 286(43):37389-98 [PubMed
] Free Access to Full Article Related Publications
Serine/threonine kinase Akt regulates key cellular processes such as cell growth, proliferation, and survival. Activation of Akt by mitogenic factor depends on phosphatidylinositol 3-kinase (PI3K). Here, we report that IKBKE (also known as IKKε and IKKi) activates Akt through a PI3K-independent pathway. IKBKE directly phosphorylates Akt-Thr308 and Ser473 independent of the pleckstrin homology (PH) domain. IKBKE activation of Akt was not affected by inhibition of PI3K, knockdown of PDK1 or mTORC2 complex. Further, this activation could be inhibited by Akt inhibitors MK-2206 and GSK690693 but not the compounds (perifosine and triciribine) targeting the PH domain of Akt. Expression of IKBKE largely correlates with activation of Akt in breast cancer. Moreover, inhibition of Akt suppresses IKBKE oncogenic transformation. These findings indicate that IKBKE is an Akt-Thr308 and -Ser473 kinase and directly activates Akt independent of PI3K, PDK1, and mTORC2 as well as PH domain. Our data also suggest that Akt inhibitors targeting the PH domain have no effect on the tumors in which hyperactive Akt resulted from elevated IKBKE.
Colas E, Perez C, Cabrera S, et al.Molecular markers of endometrial carcinoma detected in uterine aspirates.
Int J Cancer. 2011; 129(10):2435-44 [PubMed
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Endometrial cancer (EC) is the most frequent of the invasive tumors of the female genital tract. Although usually detected in its initial stages, a 20% of the patients present with advanced disease. To date, no characterized molecular marker has been validated for the diagnosis of EC. In addition, new methods for prognosis and classification of EC are needed to combat this deadly disease. We thus aimed to identify new molecular markers of EC and to evaluate their validity on endometrial aspirates. Gene expression screening on 52 carcinoma samples and series of real-time quantitative PCR validation on 19 paired carcinomas and normal tissue samples and on 50 carcinoma and noncarcinoma uterine aspirates were performed to identify and validate potential biomarkers of EC. Candidate markers were further confirmed at the protein level by immunohistochemistry and Western blot. We identified ACAA1, AP1M2, CGN, DDR1, EPS8L2, FASTKD1, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPFIBP2, PPP1R16A, RASSF7, RNF183, SIRT6, TJP3, EFEMP2, SOCS2 and DCN as differentially expressed in ECs. Furthermore, the differential expression of these biomarkers in primary endometrial tumors is correlated to their expression level in corresponding uterine fluid samples. Finally, these biomarkers significantly identified EC with area under the receiver-operating-characteristic values ranging from 0.74 to 0.95 in uterine aspirates. Interestingly, analogous values were found among initial stages. We present the discovery of molecular biomarkers of EC and describe their utility in uterine aspirates. These findings represent the basis for the development of a highly sensitive and specific minimally invasive method for screening ECs.
Guan H, Zhang H, Cai J, et al.IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-κB.
J Pathol. 2011; 223(3):436-45 [PubMed
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IκB kinase-ε (IKBKE), a member of the IκB kinase (IKK) family, has been identified as an oncogenic protein and found to be up-regulated in breast cancer, ovarian cancer and prostate cancer. Nonetheless, the expression status and functional significance of IKBKE in human glioma remain unexplored. For the first time, we have demonstrated that mRNA and protein levels of IKBKE were robustly up-regulated in glioma cell lines and human primary glioma tissues. Immunohistochemistry analysis revealed that 53.5% (38/71) paraffin-embedded archived glioma specimens exhibited high levels of IKBKE expression. Intriguingly, there was no significant difference in IKBKE expression among different grades of glioma. To understand the biological function of IKBKE in the development and progression of human glioma, glioma cells lines ectopically over-expressing IKBKE were established and tested for their responsiveness to apoptotic inducers. Our data showed that IKBKE over-expression inhibited cell apoptosis induced by UV irradiation or adriamycin and, in contrast, shRNAi-mediated suppression of IKBKE increased the sensitivity of glioma cells to the apoptotic inducers. Importantly, we found that up-regulated IKBKE could induce the expression of Bcl-2 through activating NF-κB signalling, and that, specifically, we identified IκB as a critical component for this signalling cascade. The current study suggests that up-regulation of IKBKE may represent an important molecular hallmark that is biologically and clinically relevant to the development and progression, as well as the chemo- and radio-resistance, of the disease.
Cheng Y, Geng H, Cheng SH, et al.KRAB zinc finger protein ZNF382 is a proapoptotic tumor suppressor that represses multiple oncogenes and is commonly silenced in multiple carcinomas.
Cancer Res. 2010; 70(16):6516-26 [PubMed
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Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-kappaB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-kappaB upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas.
Reuter S, Charlet J, Juncker T, et al.Effect of curcumin on nuclear factor kappaB signaling pathways in human chronic myelogenous K562 leukemia cells.
Ann N Y Acad Sci. 2009; 1171:436-47 [PubMed
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Curcumin, a natural product isolated from the plant Curcuma longa, has a diverse range of molecular targets that influence numerous biochemical and molecular cascades. Curcumin has been shown to inhibit nuclear factor kappaB (NF-kappaB) activation at several steps in the NF-kappaB signaling pathways and thereby controls numerous NF-kappaB-regulated genes involved in various diseases. In the present study, we investigated the effect of curcumin pretreatment on 84 tumor necrosis factor-alpha (TNF-alpha)-activated genes of NF-kappaB pathways in K562 cells, using a real-time PCR array. Our results show that transcription of 29 NF-kappaB-related mRNAs was significantly downregulated (CARD4, CCL2, CD40, CSF2, F2R, ICAM1, IKBKB, IKBKE, IL1A, IL1B, IL6, IL8, IRAK2, MALT1, MAP3K1, MYD88, NFKB1, NFKB2, NFKBIA, PPM1A, RAF1, RELB, STAT1, TLR3, TNF, TNFalphaIP3, TNFSF10, and TICAM1), whereas 10 mRNAs were induced (AGT, CASP1, CSF3, FOS, IFNG, IL10, TICAM2, TLR2, TLR9, and TNFRSF7). Western blot analysis of CD40, NFKB1 (p50), RELB, NFKBIA (IkappaBalpha), and IL10 as well as an IL8 secretion assay confirmed our results. Taken together, we show that curcumin regulates an impressive number of NF-kappaB genes within the different NF-kappaB signaling pathways.
Hodgkin lymphoma (HL) is derived from preapoptotic germinal center B cells, although a general loss of B cell phenotype is noted. Using quantitative reverse transcription-polymerase chain reaction and miRNA microarray, we determined the microRNA (miRNA) profile of HL and compared this with the profile of a panel of B-cell non-Hodgkin lymphomas. The two methods showed a strong correlation for the detection of miRNA expression levels. The HL-specific miRNA included miR-17-92 cluster members, miR-16, miR-21, miR-24, and miR-155. Using a large panel of cell lines, we found differential expression between HL and other B-cell lymphoma-derived cell lines for 27 miRNA. A significant down-regulation in HL compared to non-Hodgkin lymphoma was observed only for miR-150. Next, we performed target gene validation of predicted target genes for miR-155, which is highly expressed in HL and is differentially expressed between HL and Burkitt lymphoma. Using luciferase reporter assays, we validated 11 predicted miR-155 target genes in three different HL cell lines. We demonstrated that AGTR1, FGF7, ZNF537, ZIC3, and IKBKE are true miR-155 target genes in HL.
Péant B, Diallo JS, Dufour F, et al.Over-expression of IkappaB-kinase-epsilon (IKKepsilon/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell lines.
Prostate. 2009; 69(7):706-18 [PubMed
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BACKGROUND: Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that Ikappa-B kinase-epsilon (IKKepsilon/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6.
RESULTS: In this study, we report that over-expression of IKKepsilon in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKKepsilon knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKKepsilon over-expression does not induce the activation of the IKKepsilon classical targets NF-kappaB and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKKepsilon expression results in its nuclear translocation, a phenomena that is TBK1-independent.
CONCLUSIONS: This study identifies IKKepsilon as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer.
Boehm JS, Zhao JJ, Yao J, et al.Integrative genomic approaches identify IKBKE as a breast cancer oncogene.
Cell. 2007; 129(6):1065-79 [PubMed
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The karyotypic chaos exhibited by human epithelial cancers complicates efforts to identify mutations critical for malignant transformation. Here we integrate complementary genomic approaches to identify human oncogenes. We show that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to transform human cells. Using a library of activated kinases, we identify several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses reveal that one of these kinases, IKBKE (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon activates the nuclear factor-kappaB (NF-kappaB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-kappaB activation in breast cancer, implicate the NF-kappaB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.
Extensive genetic alterations have been found in many epithelial malignancies. Using three complementary genetic approaches, Boehm et al. (2007) identify IKBKE--which encodes IKKepsilon, a component of the NF-kappaB pathway--as a breast cancer oncogene.
IKK (I kappaB kinase) alpha is essential for embryonic skin development in mice. Mice deficient in IKKalpha display markedly hyperplasic epidermis that lacks terminal differentiation, and they die because of this severely impaired skin. However, the function of IKKalpha in human skin diseases remains largely unknown. To shed light on the role of IKKalpha in human skin diseases, we examined IKKalpha expression and Ikkalpha mutations in human squamous cell carcinomas (SCCs). We found a marked reduction in IKKalpha expression in poorly differentiated human SCCs and identified Ikkalpha mutations in exon 15 of Ikkalpha in eight of nine human SCCs, implying that IKKalpha is involved in development of this human skin cancer. Furthermore, in a chemical carcinogen-induced skin carcinogenesis setting, mice overexpressing human IKKalpha in the epidermis under the control of a truncated loricrin promoter developed significantly fewer SCCs and metastases than did wild-type mice. The IKKalpha transgene altered the skin microenvironment conditions, leading to elevated terminal differentiation in the epidermis, reduced mitogenic activity in the epidermis, and decreased angiogenic activity in the skin stroma. Thus, overexpression of IKKalpha in the epidermis antagonized chemical carcinogen-induced mitogenic and angiogenic activities, repressing tumor progression and metastases.
Eddy SF, Guo S, Demicco EG, et al.Inducible IkappaB kinase/IkappaB kinase epsilon expression is induced by CK2 and promotes aberrant nuclear factor-kappaB activation in breast cancer cells.
Cancer Res. 2005; 65(24):11375-83 [PubMed
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Aberrant activation of nuclear factor-kappaB (NF-kappaB) transcription factors has been implicated in the pathogenesis of breast cancer. We previously showed elevated activity of IkappaB kinase alpha (IKKalpha), IKKbeta, and protein kinase CK2 in primary human breast cancer specimens and cultured cells. A novel inducible IKK protein termed IKK-i/IKKepsilon has been characterized as a potential NF-kappaB activator. Here, we provide evidence that implicates IKK-i/IKKepsilon in the pathogenesis of breast cancer. We show IKK-i/IKKepsilon expression in primary human breast cancer specimens and carcinogen-induced mouse mammary tumors. Multiple breast cancer cell lines showed higher levels of IKK-i/IKKepsilon and kinase activity compared with untransformed MCF-10F breast epithelial cells. Interestingly, IKK-i/IKKepsilon expression correlated with CK2alpha expression in mammary glands and breast tumors derived from MMTV-CK2alpha transgenic mice. Ectopic CK2 expression in untransformed cells led to increased IKK-i/IKKepsilon mRNA and protein levels. Inhibition of CK2alpha via the pharmacologic inhibitor apigenin or upon transfection of a CK2 kinase-inactive subunit reduced IKK-i/IKKepsilon levels. Expression of a kinase-inactive IKK-i/IKKepsilon mutant in breast cancer cells reduced NF-kappaB activity as judged by transfection assays of reporters driven either by NF-kappaB elements or the promoters of two NF-kappaB target genes, cyclin D1 and relB. Importantly, the kinase-inactive IKK-i/IKKepsilon mutant reduced the endogenous levels of these genes as well as the ability of breast cancer cells to grow in soft agar or form invasive colonies in Matrigel. Thus, CK2 induces functional IKK-i/IKKepsilon, which is an important mediator of the activation of NF-kappaB that plays a critical role in the pathogenesis of breast cancer.