Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enhanced expression of matrix metalloproteinase-9 (MMP-9) correlates with invasion during tumor progression. Interferons (IFNs) inhibit MMP-9 activation in response to tumor necrosis factor-alpha (TNF-alpha), and the latter activates the MMP-9 gene through NF-kappaB. Understanding the molecular basis for MMP-9 inhibition may provide tools to control cell invasion. The data reported here show the critical role of interferon regulatory factor-1 (IRF1) in the inhibition of MMP-9. (i) IFN treatment suppresses TNF-alpha-induced MMP-9 reporter activity in STAT1(+/+) cells but not in STAT1(-/-) cells. (ii) IRF1 transfection blocks TNF-alpha-mediated MMP-9 activation. (iii) IFNs phosphorylate STAT1 and induce IRF1 but do not affect Ikappa-B degradation nor NF-kappaB nuclear translocation. (iv) Nuclear NF-kappaB (p50/p65) and IRF1, but not STAT1, bind to the MMP-9 promoter region containing an IFN-responsive-like element overlapping the NF-kappaB-binding site. (v) Recombinant IRF1, although unable to bind to an NF-kappaB consensus sequence, competes with NF-kappaB proteins for binding to the MMP-9 promoter. (vi) Conversely recombinant p50/p65 proteins reduce IRF1-DNA binding. (vii) In cells cotransfected with IRF1 and/or p65 expression vectors, an excess of IRF1 reduces MMP-9 reporter activity, whereas an excess of p65 blocks the inhibitory effect of IFN-gamma. Thus, in contrast to the known synergism between IRF1 and NF-kappaB, our data identify a novel role for IRF1 as a competitive inhibitor of NF-kappaB binding to the particular MMP-9 promoter context.
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PMID:Interferons inhibit tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 activation via interferon regulatory factor-1 binding competition with NF-kappa B. 1210 94

The serine/threonine kinase Akt/protein kinase B and the pleiotropic transcription factor nuclear factor-kappaB [NF-kappaB (p50/p65)] play important roles in the control of cell proliferation, apoptosis, and oncogenesis. Previous studies from our laboratory have shown the constitutive activation of NF-kappaB in melanoma cells. However, the mechanism of this activation is not clearly understood. The purpose of this study was to explore the role of Akt in the activation of NF-kappaB during melanoma tumor progression. Based on our observation that two of the five melanoma cell lines examined exhibit constitutive Akt activation, we evaluated Akt activation by immunohistochemistry in a series of pigmented skin lesions using an antibody specific for phospho-Akt Ser-473. Normal and slightly dysplastic nevi exhibited no significant Akt expression, in marked contrast to the dramatic Akt immunoreactivity seen in severely dysplastic nevi and melanomas (66.3% positive). When these same lesions were stained for nuclear p65, a similar expression pattern was observed. In addition, interruption of Akt activation resulted in increased apoptosis and decreased NF-kappaB promoter activity. These results indicate that activation of Akt kinase is linked to enhanced NF-kappaB nuclear localization and transactivation. We propose that activation of Akt may be an early marker for tumor progression in melanoma.
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PMID:Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. 1249 77

Aberrant nuclear factor-kappaB (NF-kappaB) activation has been implicated in the pathogenesis of several human malignancies. In this study, we determined whether NF-kappaB is constitutively activated in human prostate adenocarcinoma, and, if so, whether increased NF-kappaB activation and its binding to DNA influence tumor progression. Using tissue samples obtained during transurethral prostatic resection and paraffin-embedded sections of benign and cancer specimens, we determined the nuclear expression of NF-kappaB/p65 and NF-kappaB/p50, cytoplasmic expression of IkappaBalpha, its phosphorylation, and expression of NF-kappaB-regulated genes, specifically Bcl2, cyclin D1, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). A progressive increase in the expression of NF-kappaB/p65 (but not of p50) was observed in cancer specimens compared to benign tissue, which correlated with increasing levels of IkappaBalpha and its phosphorylation. NF-kappaB DNA-binding activity increased with increasing tumor grade and the binding complex mainly consisted of NF-kappaB/p65-p50 heterodimers. Immunohistochemical analysis showed enhanced nuclear staining for NF-kappaB/p65 in both high-grade (P <.0001) and low-grade (P <.003) cancer specimens, compared to benign tissue. The nuclear levels of NF-kappaB/p65 correlated with concurrent increase in cytosolic levels of IkappaBalpha along with NF-kappaB-dependent expression of Bcl2, cyclin D1, MMP-9, and VEGF. These results demonstrate that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and is related to tumor progression due to transcriptional regulation of NF-kappaB-responsive genes.
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PMID:Nuclear factor-kappaB/p65 (Rel A) is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. 1525 61

Interactions between malignant tumors and the host immune system shape the course of cancer progression. The molecular basis of such interactions is the subject of immense interest. Proinflammatory cytokines produced by macrophages are critical mediators of immune responses that contribute to the control of the advancement of neoplasia. We have shown that the expressions of interleukin 12 (IL-12) and inducible nitric oxide synthase (iNOS) are decreased in macrophages from mammary tumor-bearing mice. In this study, we investigated the causes of IL-12 dysregulation and found deficient nuclear factor kappaB (NFkappaB) and CCAAT/enhancer binding protein (C/EBP) expression and function in tumor bearers' peritoneal macrophages. The constitutive expressions of NFkappaB p50, c-rel, p65, and C/EBPalpha and beta, as well as the lipopolysaccharide-induced nuclear translocation and DNA binding of NFkappaB components and C/EBPalpha and beta, are profoundly impaired in macrophages from mice bearing D1-DMBA-3 tumors. Because similar findings occur with the iNOS gene, it seems that it represents a novel mechanism by which tumor-derived factors interfere with the host immune defenses.
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PMID:Diminished expression of transcription factors nuclear factor kappaB and CCAAT/enhancer binding protein underlies a novel tumor evasion mechanism affecting macrophages of mammary tumor-bearing mice. 1628 51

Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappaB (NF-kappaB), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappaB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappaB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappaB. The NF-kappaB activation induced by AEG-1 corresponded with degradation of IkappaBalpha and nuclear translocation of p65 that resulted in the induction of NF-kappaB downstream genes. Infection with an adenovirus expressing the mt32IkappaBalpha superrepressor (Ad.IkappaBalpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappaB. Our findings suggest that activation of NF-kappaB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.
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PMID:Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. 1645 7

The effect of vasoactive intestinal peptide (VIP) on cyclooxygenase-2 (COX-2) expression was analyzed in human prostate non-neoplastic (RWPE-1) as well as cancer androgen-dependent (LNCaP) and independent (PC3) cells. The three cell lines expressed VIP mRNA and VIP peptide, as measured by RT-PCR and immunochemistry, which supports an autocrine/paracrine action of VIP in the prostate gland. VIP levels were progressively higher from non-neoplastic to androgen-dependent and independent cells. Real-time RT-PCR and Western-blotting showed that VIP stimulated both COX-2 mRNA and protein expression in a faster manner as prostate cancer stage progressed (i.e. RWPE1<LNCaP<PC3 cells). Furthermore, VIP induced higher levels of COX-2 protein expression in cancer cells as compared with non-neoplastic cells. The anti-inflammatory agent curcumin blocked VIP-induced COX-2 expression in all cell lines studied supporting the involvement of nuclear factor-kappaB (NFkappaB) in such a response. In fact, VIP increased the translocation of the NFkappaB p50 subunit to the nucleus and the binding of the active form to its target gene promoter, as measured by Western-blotting and ELISA, respectively. VIP provoked faster responses according to the most aggressive status in cancer progression (androgen-independent situation). These results together with the existence of two NFkappaB sites in the COX-2 gene promoter together suggest that COX-2 may be a target for VIP in prostate cancer progression. On the other hand, VIP could be a proinflammatory cytokine acting through the NFkappaB/COX-2 system.
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PMID:Vasoactive intestinal peptide induces cyclooxygenase-2 expression through nuclear factor-kappaB in human prostate cell lines Differential time-dependent responses in cancer progression. 1743 57

The objective of our study was to determine whether TNFalpha can protect tissue resident stem cells from hydrogen peroxide (H(2)O(2)) induced apoptosis. Apoptosis was measured via fluorescence activated flow cytometry of fluorescein-conjugated Annexin V in passage 3 human ASCs. Our data show that application of 300muM H(2)O(2) for 3h induced a high number of cells to undergo apoptosis. The number of apoptotic cells significantly decreased when cells were preincubated with TNFalpha. TNFalpha caused a rapid activation of NF-kappaB within 15min as evidenced by gel shift assay (EMSA). On further dissection of the NF-small ka, CyrillicB complex, the p50 subunit which generally forms heterodimers with p65 appears to form a p50/p50 homodimer instead of conventional p50/p65 heterodimer. This novel finding has implications for tissue regeneration and might as well be of importance for cancer cell growth and tumor progression.
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PMID:TNFalpha protects tissue resident stem cells from H2O2 induced apoptosis through a novel NF-small ka, CyrillicB p50/p50 homodimer mediated signaling pathway. 1843 17

GGAP2/PIKE-A is a GTP-binding protein that can enhance Akt activity. Increased activation of the AKT and nuclear factor-kappaB (NF-kappaB) pathways have been identified as critical steps in cancer initiation and progression in a variety of human cancers. We have found significantly increased expression GGAP2 in the majority of human prostate cancers and GGAP2 expression increases Akt activation in prostate cancer cells. Thus, increased GGAP2 expression is a common mechanism for enhancing the activity of the Akt pathway in prostate cancers. In addition, we have found that activated Akt can bind and phosphorylate GGAP2 at serine 629, which enhances GTP binding by GGAP2. Phosphorylated GGAP2 can bind the p50 subunit of NF-kappaB and enhances NF-kappaB transcriptional activity. When expressed in prostate cancer cells, GGAP2 enhances proliferation, foci formation, and tumor progression in vivo. Thus, increased GGAP2 expression, which is present in three quarters of human prostate cancers, can activate two critical pathways that have been linked to prostate cancer initiation and progression.
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PMID:GGAP2/PIKE-a directly activates both the Akt and nuclear factor-kappaB pathways and promotes prostate cancer progression. 1917 82

The (HER2/Neu) ErbB2 oncogene is commonly overexpressed in human breast cancer and is sufficient for mammary tumorigenesis in transgenic mice. Nuclear factor (NF)-kappaB activity is increased in both human and murine breast tumors. The immune response to mammary tumorigenesis may regulate tumor progression. The role of endogenous mammary epithelial cell NF-kappaB had not previously been determined in immune-competent animals. Furthermore, the role of the NF-kappaB components, p50 and p65, in tumor growth was not known. Herein, the expression of a stabilized form of the NF-kappaB-inhibiting IkappaBalpha protein (IkappaBalphaSR) in breast tumor cell lines that express oncogenic ErbB2 inhibited DNA synthesis and growth in both two- and three-dimensional cultures. Either NF-kappaB inhibition or selective silencing of p50 or p65 led to a loss of contact-independent tumor growth in vitro. IkappaBalphaSR reversed the features of the oncogene-induced phenotype under three-dimensional growth conditions. The NF-kappaB blockade inhibited ErbB2-induced mammary tumor growth in both immune-competent and immune-deficient mice. These findings were associated with both reduced tumor microvascular density and a reduction in the amount of vascular endothelial growth factor. The expression of IkappaBalphaSR in breast cancer tumors inhibited angiogenesis. Thus, mammary epithelial cell NF-kappaB activity enhances ErbB2-mediated mammary tumorigenesis in vivo by promoting both growth and survival signaling via the promotion of tumor vasculogenesis.
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PMID:Nuclear factor-kappaB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo. 1934 72

NFkappaB is an inducible transcription factor that controls kinetically complex patterns of gene expression. Several studies reveal multiple pathways linking NFkappaB to the promotion and progression of various cancers. Despite extensive interest and characterization, many NFkappaB controlled genes still remain to be identified. We used chromatin immunoprecipitation combined with microarray technology (ChIP/chip) to investigate the dynamic interaction of NFkappaB with the promoter regions of 100 genes known to be expressed in mitogen-induced T-cells. Six previously unrecognized NFkappaB controlled genes (ATM, EP300, TGFbeta, Selectin, MMP-1 and SFN) were identified. Each gene is induced in mitogen-stimulated T-cells, repressed by pharmacological NFkappaB blockade, reduced in cells deficient in the p50 NFkappaB subunit and dramatically repressed by RNAi specifically designed against cRel. A coregulatory role for Ets transcription factors in the expression of the NFkappaB controlled genes was predicted by comparative promoter analysis and confirmed by ChIP and by functional disruption of Ets. NFkappaB deficiency produces a deficit in ATM function and DNA repair indicating an active role for NFkappaB in maintaining DNA integrity. These results define new potential targets and transcriptional networks governed by NFkappaB and provide novel functional insights for the role of NFkappaB in genomic stability, cell cycle control, cell-matrix and cell-cell interactions during tumor progression.
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PMID:Identification of new Rel/NFkappaB regulatory networks by focused genome location analysis. 1950 93


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