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)

Tumor necrosis factor alpha (TNFalpha) is thought to contribute to the blunted erythropoietin (Epo) production in inflammatory diseases. The present study was carried out to find out as to whether the 55 kD (TNF-RI) or the 75 kD (TNF-RII) receptor is responsible for the TNFalpha-induced inhibition of hepatic Epo synthesis. When the effects of two receptor-specific mutants were compared, only the TNF-RI-specific isoform proved to suppress the formation of immunoreactive Epo in the human hepatoma cell lines HepG2 and Hep3B, similar to the effect of wild-type TNFalpha. Anti-TNFalpha antibody restored Epo production in TNFalpha- or TNF-RI mutant-treated cultures. By gel shift assay NF-kappaB binding to DNA was demonstrated following the addition of TNFalpha or TNF-RI-specific mutant to HepG2 cells, while the TNF-RII-specific mutant was ineffective. Finally, immunoreactive TNF-RI, but not TNF-RII, fragments were measurable in cell culture supernatants. Taken together, these results suggest that the inhibition of hepatic Epo production by TNFalpha is mediated by TNF-RI signaling.
 ...
PMID:Tumor necrosis factor p55 receptor (TNF-RI) mediates the in vitro inhibition of hepatic erythropoietin production. 1002 60

TNF alpha and IL-1 alpha are thought to contribute to impaired anabolism in a variety of clinical states, including sepsis, cancer cachexia and the AIDS wasting syndrome. We asked whether cytokines exert direct effects on hepatic production of IGFBP-1, an important modulator of IGF bioavailability. C57BL/6 mice were treated with 100 micrograms/kg of recombinant IL-1 alpha or TNF alpha by intraperitoneal injection. Western ligand blotting and immunoprecipitation with specific antisera revealed that serum levels of IGFBP-1 (but not IGFBP-2, -3, -4, -5 or -6) are increased approximately 4 fold 2 h after treatment and then decline. Northern blotting confirms that hepatic IGFBP-1 mRNA abundance also is increased acutely in both IL-1 alpha- and TNF alpha-treated animals. Similar results obtained in adrenalectomized mice indicate that adrenal activation is not required for this effect. Cell culture studies show that cytokines exert direct effects on the production of IGFBP-1 by HepG2 hepatoma cells, increasing IGFBP-1 levels in conditioned medium and the abundance of IGFBP-1 mRNA approximately 3-fold. In contrast, transient transfection studies with IGFBP-1 promoter/luciferase reporter gene constructs show that IGFBP-1 promoter activity is reduced after 18 hr cytokine treatment. We conclude that IL-1 alpha and TNF alpha increase circulating levels of IGFBP-1, reflecting direct effects on hepatic IGFBP-1 mRNA abundance. Stimulation of hepatic IGFBP-1 production may contribute to alterations in IGF bioactivity and impaired anabolism in clinical conditions where cytokine production is high. Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1.
 ...
PMID:Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro. 1022 4

Liver carcinogenesis is associated with striking changes in the integrin repertoire of hepatocytes, including the overexpression of the laminin and collagen receptors alpha1beta1 and the de novo induction of the laminin receptor alpha6beta1. Our aim was to analyze the role of pro-inflammatory cytokines, interferons and fibrogenic cytokines TGF-beta and FGF2 in the regulation of the expression of beta1 integrins by neoplastic hepatocytes. The 2 human hepatocellular cell lines HepG2 and Hep3B were used as models. Integrin expression was assessed by qualitative methods (immunocytochemistry, Western blotting) and semi-quantitative techniques (FACS, cellular ELISA), before and after stimulation by TNFalpha, IL1-beta, TGF-beta, FGF2, interferon gamma and interferon alpha-2b. HepG2 and Hep3B constitutively expressed alpha1, alpha2, alpha6 and beta1 chains. A 24 to 48-hr stimulation with pro-inflammatory cytokines, TGF-beta and FGF2 induced a significant increase in the concentrations of all integrin chains. The maximum induction was registered for beta1 chain, which presented increases amounting up to 3, 4 and 7 times the control values in the presence of, respectively, TNF alpha/IL1-beta, TGF-beta and FGF2. Interferons had no direct effect on integrin expression and partially antagonized the effects of TNF alpha and TGF-beta. The increased concentrations of integrin chains were associated with an increased membrane expression of the corresponding dimers and with an increased adhesion of stimulated hepatocytes to laminin, which was antagonized by neutralizing anti-beta1 and anti-alpha6 antibodies. Finally, anti-alpha6 antibody inhibited the migration of HepG2 and Hep3B cells in reconstituted basement membrane. Our results suggest that the stimulation of alpha6beta1 integrin expression in hepatocarcinoma cells is essential for cell adhesion and migration.
 ...
PMID:alpha6beta1 integrin expression in hepatocarcinoma cells: regulation and role in cell adhesion and migration. 1050 89

Fibronectin (Fn) is a high molecular weight glycoprotein and acute phase reactant that contributes to a variety of cellular activities including proliferation and wound healing. Production of Fn is influenced by cytokines such as IL-1alpha, IL-6 and TNF -alpha, and in serum Fn levels can function as an indicator of sepsis and reticulo-endothelial function. Here we describe the production of a panel of mAb to chicken Fn and give evidence that a chicken hepatocellular carcinoma cell line, LMH, constitutively expresses Fn. A capture ELISA to measure chicken Fn was developed using an IgG1 mAb (AV62) as the capture Ab, and biotinylated AV63 (IgG2b) as the detecting Ab. This study identified a single commercially available mAb directed against human Fn that also recognised chicken Fn. By contrast, the anti-chicken Fn mAbs did not cross-react with either human or bovine Fn.
 ...
PMID:Development and use of monoclonal antibodies to chicken fibronectin to show that the chicken hepatocellular carcinoma cell line, LMH, constitutively expresses fibronectin. 1075 32

Recombinant preparations of human anti-inflammatory cytokines: IL-4, IL-13 and IL-10, inhibited LPS-induced synthesis of TNFalpha and IL-6 in the whole human blood tested in vitro. These cytokines also inhibited LPS-induced IL-6 and TNF mRNA accumulation in isolated human blood monocytes/macrophages. On the other hand, similar concentrations of IL-4 and IL-13 (but not IL-10) enhanced synthesis of IL-6 in cultured human umbilical vein endothelial cells (HUVEC). In human hepatoma HepG2 cells IL-4 and IL-13 (but not IL-10) inhibited IL-6-induced synthesis of haptoglobin. These differential responses to the tested anti-inflammatory cytokines were observed at mRNA and protein levels and may reflect cell specificities in signalling pathways and gene expression. When HUVEC and HepG2 cells were cultured together and stimulated with LPS the addition of IL-4 or IL-13 resulted in the reduction of LPS-induced and IL-6-mediated haptoglobin synthesis. Thus in co-culture the inhibitory effects of IL-4 or IL-13 on HepG2 cells prevail over stimulation of IL-6 synthesis in HUVEC.
 ...
PMID:Differential responses of hematopoietic and non-hematopoietic cells to anti-inflammatory cytokines: IL-4, IL-13 and IL-10. 1101 59

Many tumors, including hepatocellular carcinomas (HCCs), resist Fas-mediated cell death, which is one of the effector mechanisms in the host's anti-tumor response; however, this resistance can be abolished by interferon-gamma (IFN-gamma). IFN-gamma may sensitize Fas-mediated cell death in several ways, but the exact mechanism in HCCs is uncertain. In this study, we thoroughly investigated the effect of IFN-gamma on the susceptibility of one human normal liver cell line and 12 HCC cell lines to Fas-mediated cell death. We also investigated the effect of IFN-gamma on the expression of various apoptosis-related genes such as the Fas/TNF-related genes, the bcl-2 family, and the caspase family of genes. Although most cell lines showed considerable constitutive expression of Fas, all tested cell lines resisted Fas-mediated cell death without IFN-gamma. When cells were pretreated with IFN-gamma, only three cell lines were made significantly susceptible to Fas-mediated cell death (SNU-354, SNU-387 and SNU-423); the other 10 cell lines were not affected. IFN-gamma increased the mRNA expression of Fas, TRAIL and caspase-1, and surface Fas was also increased. The strongly sensitized cell lines (SNU-354, SNU-387 and SNU-423) showed a particularly potent increment in surface Fas after IFN-gamma treatment (increase in surface Fas > 1.7-fold). This result enabled us to conclude that a potent increment of surface Fas expression is a major sensitizing mechanism of IFN-gamma. We conclude that IFN-gamma cannot play a sensitizing role in most HCC cell lines and that IFN-gamma makes HCC cells susceptible to Fas-mediated cell death through a marked up-regulation of surface Fas in some HCC cells.
 ...
PMID:Effect of interferon-gamma on the susceptibility to Fas (CD95/APO-1)-mediated cell death in human hepatoma cells. 1131 6

Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis worldwide and may lead to the development of hepatocellular carcinoma. However, the mechanism of development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. In the present study, we have investigated the effect of nonstructural protein 5A (NS5A) on TNF- and Fas-mediated apoptosis in the liver of transgenic mice. For this purpose, transgenic mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a detectable histological change in the liver at 8-12 weeks of age. Intraperitoneal injection of recombinant TNF induced hepatic injury and apoptosis in normal mice. In contrast, transgenic mice expressing NS5A protein were protected against hepatic apoptosis after injection of TNF. However, injection of anti-Fas antibody into transgenic mice did not significantly influence hepatic apoptosis compared to the normal littermates. These results suggested distinct effects of TNF and anti-Fas antibody in transgenic mice expressing NS5A. We subsequently investigated the effect of NS5A in signaling pathways involved in these two cytokine-mediated apoptosis. A physical association between NS5A and TRADD was observed by pull-down assay, coimmunoprecipitation, and colocalization experiments. Furthermore, NS5A prevented the association between TRADD and FADD and blocked TRADD-mediated NF-kappaB activation. Together, our results suggest that NS5A impairs TNF-mediated apoptosis by interfering upstream of the signal transduction pathway and may play a role in HCV-mediated pathogenesis.
 ...
PMID:Hepatitis C virus NS5A protein impairs TNF-mediated hepatic apoptosis, but not by an anti-FAS antibody, in transgenic mice. 1188 69

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, selectively induce apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2 and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. However, the determining factors of the sensitivity to TRAIL-induced apoptosis are not clearly understood. Herein, we investigated the expression of TRAIL-R, c-FLIP, FADD-like interleukin-1beta-converting enzyme inhibitory protein, and TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) cell lines. Seven of ten HCC cell lines showed resistance to TRAIL-induced apoptosis and five of seven TRAIL-resistant cell lines became sensitive to TRAIL by co-treatment with cycloheximide. In HCC cell lines, their TRAIL resistance did not correlate with the basal expression level of TRAIL receptors or c-FLIP, however, in human tissues, TRAIL-R1 and TRAIL-R2 expressions were notably decreased compared to normal counterpart. Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines. Inhibition of nuclear factor K B (NF-kappaB) by SN50, a peptide inhibitor of NF-KB activity, had no effect on TRAIL-induced apoptosis in HCC cells. These results suggest that (a) the majority of human HCC cell lines are resistant to TRAIL-induced apoptosis and cycloheximide-sensitive short-lived antiapoptotic molecule(s) is responsible for this resistance, (b) the expression of TRAIL-R1 and TRAIL-R2 is reduced in HCC tissues, and the increased expression of TRAIL-R1 may be a mechanism of cisplatininduced sensitization to TRAIL-induced apoptosis in some HCC cells, and (c) the activation of NF-kappaB may not be involved in the TRAIL resistance of HCC cells
 ...
PMID:Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. 1208 86

Tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) are important mediators in cancer cachexia; however, the expression of these cytokines and their receptors in tumor-bearing animals is poorly characterized. We analyzed expression of TNF-alpha, IL-6, tumor necrosis factor (TNF-RI, TNF-RII) and interleukin 6 (IL-6R) receptors in the brain, kidney, spleen, liver, muscle, ascite tumors and serum, from Yoshida AH-130 hepatoma-bearing rats. TNF-alpha increased in the brain, spleen, liver, and muscle of cachectic animals; IL-6 increased in the liver and muscle. AH-130 cells expressed a good level of TNF-alpha; on the contrary, no TNF-alpha or IL-6 protein was detected in the serum of either tumor-bearing or control animals. TNF-RI mRNA was up-regulated in the spleen, liver and muscle of tumor-bearing rats. TNF-RI protein levels confirmed up-regulation in the spleen and liver, but failed to detect any increase in the muscle. Western blotting against TNF-RI revealed two bands of lower molecular weight in cachectic muscle, suggesting proteolysis involving TNF-RI. No significant increase of either TNF-RII or IL-6R was observed. This is the first demonstration of a selective up-regulation of TNF-RI in cancer cachexia and suggests that local production of TNF-alpha and IL-6 is a corner-stone in the induction/maintenance of this syndrome.
 ...
PMID:Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia. 1285 92

Human hepatocellular carcinomas (HCCs) show resistance to apoptosis mediated by several death receptors. Because cellular FLICE/caspase-8-inhibitory protein (cFLIP) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits death signaling mediated by all known death receptors, including Fas, TNF-receptor (TNF-R), and TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs), we investigated the expression and function of cFLIP in human HCCs. We found that cFLIP is constitutively expressed in all human HCC cell lines and is expressed more in human HCC tissues than in nontumor liver tissues. Metabolic inhibitors, actinomycin D (ActD) or cycloheximide (CHX), dramatically rendered HCC cells sensitive to Fas-mediated apoptosis. Neither caspase-8 nor caspase-3 was activated by agonistic anti-Fas antibody alone, but both caspases were activated by Fas stimulation in the presence of ActD or CHX, indicating the importance of caspase-8 inhibitors that are sensitive to metabolic inhibitors. Actually, cFLIP expression was decreased in ActD or CHX treatment. cFLIP down-regulation induced by cFLIP antisense oligodeoxynucleotides sensitized HLE cells to Fas, TNF-R, and TRAIL-R-mediated apoptosis. Furthermore, cFLIP over-expression activated nuclear factor (NF)-kappaB and cFLIP down-regulation attenuated NF-kappaB activation induced by TNF-alpha or TRAIL. Pretreatment with pan-caspase-inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD-fmk), restored NF-kappaB activity attenuated by cFLIP down-regulation. cFLIP expression was increased by TNF-alpha, TRAIL, or vascular endothelial growth factor but decreased by wortmannin, indicating that cFLIP expression is regulated by both the NF-kappaB and phosphatidylinostiol-3 kinase (PI-3)/Akt pathways. These results suggest that cFLIP plays an important role in cell survival not simply by inhibiting death-receptor-mediated apoptosis but also by regulating NF-kappaB activation in human HCCs.
 ...
PMID:Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma. 1286 Oct 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>