Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cDNA encoding hepatitis C virus NS5A protein was isolated from the serum of a patient with hepatocellular carcinoma. The NS5A(HCC) was localized in both the cytoplasmic and nuclear fractions of Huh-7 cells. Immunoprecipitation and electrophoresis experiments showed four major phosphorylated species of NS5A(HCC), p58, p56, p53, and p50. Two mutants (NS5A(HCC-NLSmt) and NS5A(HCC-TSmt)) carrying mutations on the putative nuclear localization signal were engineered. NS5A(HCC-NLSmt) was localized exclusively in the cytoplasm, whereas some forms of NS5A(HCC-TSmt) can be transported into the nucleus. These NS5A(HCC) mutant proteins were capable of transactivating c-fos and SV40 promoters. However, the transactivation efficiency was not dependent on its capability of nuclear localization. Subsequently, interaction between NS5A(HCC) mutants and Grb2 was studied. While capable of transactivating oncogenic promoters, NS5A(HCC-TSmt) could not interact with Grb2. Our results suggested that other cytosolic pathways independent of Grb2-mediated mechanisms were involved in the transactivation activity of HCV NS5A.
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PMID:Characterization of a HCV NS5A protein derived from a patient with hepatoma. 1562 44

C-reactive protein (CRP) is an acute phase protein produced by hepatocytes. A minor elevation in the baseline levels of serum CRP is considered an indicator of chronic inflammation. In hepatoma Hep3B cells, IL-6 induces CRP expression by activating transcription factors STAT3 and C/EBPbeta. IL-1 synergistically enhances the effects of IL-6. The first 157 bp of the CRP promoter are sufficient for IL-1 synergy. Previously, NF-kappaB, a transcription factor activated by IL-1beta in Hep3B cells, has been shown to increase endogenous CRP expression. The purpose of this study was to investigate the possible action of NF-kappaB on the 157 bp of the proximal promoter. In this study we show that NF-kappaB requires and acts synergistically with C/EBPbeta on the CRP-proximal promoter to regulate CRP expression. We located the regulatory element that consisted of overlapping binding sites for NF-kappaB (p50-p50 and p50-p65) and OCT-1. The kappaB site was responsible for the synergy between NF-kappaB and C/EBPbeta and was also necessary for the CRP transactivation by C/EBPbeta through the C/EBP site. Mutation of the kappaB site decreased the synergistic effect of IL-1beta on IL-6-induced CRP expression. Basal CRP expression increased dramatically when binding of both OCT-1 and NF-kappaB was abolished. Combined data from luciferase transactivation assays and EMSA lead us to conclude that the binding of OCT-1 to the promoter, facilitated by p50-p50 in a novel way, represses, whereas replacement of OCT-1 by p50-p65 induces CRP transcription in cooperation with C/EBPbeta. This model for CRP expression favors the variation seen in baseline serum CRP levels in a normal healthy population.
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PMID:Regulation of basal and induced expression of C-reactive protein through an overlapping element for OCT-1 and NF-kappaB on the proximal promoter. 1611 32

Wy-14,643 (WY) is a hypolipidemic drug that induces hepatic peroxisome proliferation and tumors in rodents. We previously showed that peroxisome proliferators increase NF-kappaB DNA binding activity in rats, mice, and hepatoma cell lines, and that mice deficient in the p50 subunit of NF-kappaB had much lower cell proliferation in response to the peroxisome proliferator ciprofibrate. In this study we examined the promotion of hepatocarcinogenesis by WY in the p50 knockout (-/-) mice. The p50 -/- and wild type mice were first administered diethylnitrosamine (DEN) as an initiating agent. Mice were then fed a control diet or a diet containing 0.05% WY for 38 weeks. Wild-type mice receiving DEN only developed a low incidence of tumors, and the majority of wild-type mice receiving both DEN and WY developed tumors. However, no tumors were seen in any of the p50 -/- mice. Cell proliferation and apoptosis were measured in hepatocytes by BrdU labeling and the TUNEL assay, respectively. Treatment with DEN + WY increased both cell proliferation and apoptosis in both the wild-type and p50 -/- mice; DEN treatment alone has no effect. In the DEN/WY-treated mice, cell proliferation and apoptosis were slightly lower in the p50 -/- mice than in the wild-type mice. These data demonstrate that NF-kappaB is involved in the promotion of hepatic tumors by the peroxisome proliferator WY; however, the difference in tumor incidence could not be attributed to alterations in either cell proliferation or apoptosis.
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PMID:Inhibition of hepatocarcinogenesis by the deletion of the p50 subunit of NF-kappaB in mice administered the peroxisome proliferator Wy-14,643. 1643

Nuclear factor-kappaB (NF-kappaB) has been recognized to play a critical role in cell survival and inflammatory processes. It has become a target for intense drug development for the treatment of cancer, inflammatory, and autoimmune diseases. Here, we describe a potent NF-kappaB inhibitor, eriocalyxin B (Eri-B), an ent-kauranoid isolated from Isodon eriocalyx, an anti-inflammatory remedy. The presence of two alpha,beta-unsaturated ketones give this compound the uniqueness among the ent-kauranoids tested. Eri-B inhibited the NF-kappaB transcriptional activity but not that of cAMP response element-binding protein. It suppressed the transcription of NF-kappaB downstream gene products including cyclooxygenase-2 and inducible nitric-oxide synthase induced by tumor necrosis factor-alpha or lipopolysaccharide in macrophages and hepatocarcinoma cells. Chromatin immunoprecipitation assay indicated that Eri-B selectively blocked the binding between NF-kappaB and the response elements in vivo without affecting the nuclear translocation of the transcription factor. Down-regulation of the endogenous p65 protein sensitized the cells toward the action of the compound. Furthermore, in vitro binding assays suggested that Eri-B reversibly interfered with the binding of p65 and p50 subunits to the DNA in a noncompetitive manner. In summary, this study reveals the novel action of a potent NF-kappaB inhibitor that could be potentially used for the treatment of a variety of NF-kappaB-associated diseases. Modification of the structure of this class of compounds becomes the key to the control of the behavior of the compound against different cellular signaling pathways.
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PMID:Eriocalyxin B inhibits nuclear factor-kappaB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner. 1694 Apr 13

Regulation of basal and cytokine (IL-6 and IL-1beta)-induced expression of C-reactive protein (CRP) in human hepatoma Hep3B cells occurs during transcription. A critical transcriptional regulatory element on the CRP promoter is a C/EBP binding site overlapping a NF-kappaB p50 binding site. In response to IL-6, C/EBPbeta and p50 occupy the C/EBP-p50 site on the CRP promoter. The aim of this study was to identify the transcription factors occupying the C/EBP-p50 site in the absence of C/EBPbeta. Accordingly, we treated Hep3B nuclear extract with a C/EBP-binding consensus oligonucleotide to generate an extract lacking active C/EBPbeta. Such treated nuclei contain only C/EBPzeta (also known as CHOP10 and GADD153) because the C/EBP-binding consensus oligonucleotide binds to all C/EBP family proteins except C/EBPzeta. EMSA using this extract revealed formation of a C/EBPzeta-containing complex at the C/EBP-p50 site on the CRP promoter. This complex also contained RBP-Jkappa, a transcription factor known to interact with kappaB sites. RBP-Jkappa was required for the formation of C/EBPzeta-containing complex. The RBP-Jkappa-dependent C/EBPzeta-containing complexes were formed at the C/EBP-p50 site on the CRP promoter in the nuclei of primary human hepatocytes also. In luciferase transactivation assays, overexpressed C/EBPzeta abolished both C/EBPbeta-induced and (IL-6 + IL-1beta)-induced CRP promoter-driven luciferase expression. These results indicate that under basal conditions, C/EBPzeta occupies the C/EBP site, an action that requires RBP-Jkappa. Under induced conditions, C/EBPzeta is replaced by C/EBPbeta and p50. We conclude that the switch between C/EBPbeta and C/EBPzeta participates in regulating CRP transcription. This process uses a novel phenomenon, that is, the incorporation of RBP-Jkappa into C/EBPzeta complexes solely to support the binding of C/EBPzeta to the C/EBP site.
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PMID:A novel RBP-J kappa-dependent switch from C/EBP beta to C/EBP zeta at the C/EBP binding site on the C-reactive protein promoter. 1751 80

Nuclear factor kappaB (NF-kappaB) and activator protein 1 are transcription factors involved in the regulation of cell proliferation that play important roles in tumorigenesis. We investigated whether these two factors cooperate for transcriptional regulation of cyclin D1 (CCND1), a gene whose deregulation is critical during carcinogenesis. We demonstrate that overexpression of JunD in human hepatocarcinoma cells strongly activates transcription mediated by the kappaB2 site of the CCND1 promoter in reporter assays, in a manner strictly dependent on the presence of NF-kappaB proteins. Serum stimulation increased the expression of p65, p50, c-Fos, c-Jun and JunD and induced the recruitment of p65, p50 and JunD to the kappaB2 site of the promoter in DNA pull-down assays. Chromatin immunoprecipitation (ChIP) analysis confirmed the serum-induced recruitment of JunD to the promoter in vivo and showed that the presence of JunD was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of JunD recruitment. Serum-induced activation of protein binding to kappaB2 correlated with high levels of phosphoinositide-dependent protein kinase-1 (PDK-1) phosphorylation. Both LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), and overexpression of a dominant-negative form of PDK-1 inhibited the JunD-stimulating effect in reporter assays. LY294002 also prevented the serum-induced recruitment of JunD, but not p65 or p50 to the promoter in ChIP assay. JunD-p65 complexes, identified in vivo by co-immunoprecipitation, were decreased by LY294002 and by small interfering RNA inhibition of PDK-1. Taken together, our data demonstrate a PI3K/PDK-1-dependent functional cooperation of NF-kappaB and JunD in the transcriptional regulation of CCND1 by serum.
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PMID:Jun D cooperates with p65 to activate the proximal kappaB site of the cyclin D1 promoter: role of PI3K/PDK-1. 1817 38

The link of proto-oncogenic protein Wnt-1 production with NF-kappaB activation has been functionally demonstrated in PC12 cells, a rat pheochromocytoma cell line of neural crest lineage, while it is not yet verified in human cells. The link can be indirectly supported in our previous report that functional proteomics identifies enhanced expression of NF-kappaB-associated Wnt-1 production in human hepatocellular carcinoma tissues. This study aimed to further validate this link in human cells using anti-sense strategy. The effects of sequence-specific anti-sense morpholino oligonucleotides (ONs) targeting against pre-mRNA sequences of human p50 and p65 subunits of NF-kappaB as well as Wnt-1 genes were investigated. It revealed that all the three morpholino ONs inhibited NF-kappaB activation in human hepatoblastoma cell line HepG2 cells along with decreased Wnt-1 production. Chromatin immunoprecipitation assay ascertained the direct binding of NF-kappaB-p50 to the Wnt-1 promoter. Additionally, anti-P50 and anti-P65 morpholino ONs also repressed the phosphorylation of Ikappa Balpha which temporarily correlated with the inhibition of NF-kappaB activation accompanied by decreased Wnt-1 production by HepG2 cells. In summary, NF-kappaB activation is critically involved in the production of Wnt-1 by HepG2 cells. These results may have important oncology implications in treating patients with NF-kappaB-associated Wnt-1-producing cancers.
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PMID:Anti-sense morpholino oligonucleotide assay shows critical involvement for NF-kappaB activation in the production of Wnt-1 protein by HepG2 cells: oncology implications. 1846 73

There are five nuclear factor-kappaB (NF-kappaB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF-kappaB, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF-kappaB pathway has been observed, providing ample experimental support for the tumor-promoting function of NF-kappaB in various models of cancer. NF-kappaB has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF-kappaB, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF-kappaB has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF-kappaB promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF-kappaB are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF-kappaB factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response.
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PMID:NF-kappaB in liver diseases: a target for drug therapy. 1893 12

The human inducible nitric oxide synthase (hiNOS) gene is regulated by nuclear factor kappaB (NF-kappaB) and has recently been shown to be a target of the Wnt/beta-catenin pathway. In this study, we tested the hypothesis that Wnt/beta-catenin signaling might regulate cytokine- or tumor necrosis factor alpha (TNFalpha)-induced hiNOS expression through interaction with NF-kappaB. A cytokine mixture of TNFalpha + interleukin (IL)-1beta + IFNgamma induced a 2- to 3-fold increase in hiNOS promoter activity in HCT116 and DLD1 colon cells, but produced a 2-fold decrease in SW480 colon cancer cells. A similar differential activity was seen in liver cancer cells (HepG2, Huh7, and Hep3B). Overexpression of beta-catenin produced a dose-dependent decrease in NF-kappaB reporter activity and decreased cytokine mixture-induced hiNOS promoter activity. Gel shift for TNFalpha-induced hiNOS NF-kappaB activation showed decreased p50 binding and decreased NF-kappaB reporter activity in the beta-catenin-mutant HAbeta18 cells. Conversely, enhanced p50 binding and increased NF-kappaB reporter activity were seen in HAbeta85 cells, which lack beta-catenin signaling. Coimmunoprecipitation confirmed that beta-catenin complexed with both p65 and p50 NF-kappaB proteins. NF-kappaB-dependent Traf1 protein expression also inversely correlated with the level of beta-catenin. Furthermore, SW480 cells stably transformed with wild-type adenomatous polyposis coli showed decreased beta-catenin protein and increased TNFalpha-induced p65 NF-kappaB binding as well as iNOS and Traf1 expression. Finally, beta-catenin inversely correlated with iNOS and Fas expression in vivo in hepatocellular carcinoma tumor samples. Our in vitro and in vivo data show that beta-catenin signaling inversely correlates with cytokine-induced hiNOS and other NF-kappaB-dependent gene expression. These findings underscore the complex role of Wnt/beta-catenin, NF-kappaB, and iNOS signaling in the pathophysiology of inflammation-associated carcinogenesis.
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PMID:Wnt/beta-catenin signaling regulates cytokine-induced human inducible nitric oxide synthase expression by inhibiting nuclear factor-kappaB activation in cancer cells. 1938

Elevated circulating levels of acute phase proteins (APP) are associated with inflammation and inflammatory disorders such as cardiovascular disease. APP are mainly synthesised by hepatocytes and their transcription is induced by pro-inflammatory cytokines such as interleukin-1 (IL-1). The molecular mechanisms underlying the IL-1-induced expression of key transcription factors implicated in the regulation of APP are poorly understood. We have investigated this aspect using the CCAAT/enhancer binding protein-delta (C/EBPdelta) as a model gene. IL-1 induced the expression of C/EBPdelta mRNA and protein in the human hepatoma Hep3B cell line, a widely employed model system for studies on cytokine signalling in relation to the expression of APP. The IL-1-mediated induction of C/EBPdelta expression was attenuated in the presence of pharmacological inhibitors against c-Jun N-terminal kinase (JNK) (curcumin and SP600125), casein kinase 2 (CK2) (apigenin) and nuclear factor-kappaB (NF-kappaB) (NF-kappaB activation inhibitor). RNA interference assays showed significant attenuation of the IL-1-induced expression of C/EBPdelta following knockdown of the p50 and p65 subunits of NF-kappaB. IL-1 induced NF-kappaB DNA binding and activation by this transcription factor and this was attenuated by curcumin and apigenin. Taken together, these results suggest a potentially crucial role for NF-kappaB in the IL-1-induced expression of C/EBPdelta, and thereby downstream APP genes regulated by this transcription factor.
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PMID:Requirement for nuclear factor kappa B signalling in the interleukin-1-induced expression of the CCAAT/enhancer binding protein-delta gene in hepatocytes. 1980 21


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