UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that release of cytokines during inflammatory states such as septic shock leads to hypocholesterolemia. To examine whether tumor necrosis factor alpha (TNF), which is the major cytokine in inflammatory disease, causes hypocholesterolemia, we measured serum levels of total (bioactive and receptor-bound) TNF, cholesterol, Apo B, and Apo A1 in seven patients with septic shock over a period of 8 days. Since elevated serum TNF levels are accompanied by the release of soluble TNF receptors, levels of TNF receptors p55 and p75 were also measured. Patients with septic shock had significantly higher serum TNF and TNF receptor levels compared with healthy controls. Increased cytokine levels were accompanied by a significant decline in total serum cholesterol apolipoprotein A1 and B. In vitro studies with cultured human skin fibroblasts, human umbilical vein endothelial cells, and HepG2 hepatoma cells showed that TNF increased the degradation of 125I-labeled low-density lipoprotein in all the cell lines tested. Recombinant soluble TNF receptors inhibited the TNF-induced stimulation of low-density lipoprotein receptor in a concentration-dependent manner. However, the calculated ratio of TNF receptors to total TNF measured in serum of these patients was not able to counteract the stimulatory effect of TNF, possibly due to the higher molar excess of TNF receptors required to achieve this effect in vitro. Our data strengthen the hypothesis that serum values of total TNF determine the extent of hypocholesterolemia during sepsis and septic shock despite the presence of a high concentration of TNF receptors. Studies with recombinant TNF also confirm the role of TNF in hypocholesterolemia in inflammation.
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PMID:Association of serum tumor necrosis factor levels with decrease of cholesterol during septic shock. 984 Jun 52

Differential cDNA displays between hepatocellular carcinoma and adjacent non-malignant tissues have previously detected a PCR product, hIRH (human intercrine reduced in hepatomas), equivalent to SDF1alpha/PBSF whose mRNA was lost from human hepatocellular carcinoma and other malignant and pre-malignant samples and malignant cell lines. There are no reports to date of the mRNA status of the receptor for hIRH/SDF1alpha/PBSF, CXCR4 in malignant tissues. We report here that there is a reduction in the mRNA expression of CXCR4 in hepatocellular carcinoma as estimated by Northern blot and RT-PCR and compared to the adjacent non-malignant tissue. The average (mean SD) tumor/normal ratio for CXCR4 mRNA expression, determined by RT-PCR, was 0.65 0.36 in 10 pairs of hepatocellular carcinomas. There was no consistent loss of CXCR4 mRNA expression in a range of malignant cell lines. The 3'-non-coding region of hIRH, had typical early response gene element sequences. Despite the presence of these 3'-elements there was no induction of hIRH gene expression in human lung carcinoma A549 cells by tumor necrosis factor alpha, interleukin-2, lipopolysaccharide or phorbol myristic acetate, nor in human melanoma cell line SB-2 by uv irradiation, under conditions which induced the homologue CXC intercrine IL-8 expression. Furthermore, there was no induction of hIRH gene expression, but rather a suppression, upon serum or cytokine addition to serum-deprived fibroblast cell lines, to an in vitro mouse bone marrow preparation, and to monocytic cell line THP-1.
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PMID:Reduced expression of the CXCR4 receptor mRNA in hepatocellular carcinoma and lack of inducibility of its ligand alpha-chemokine hIRH/SDF1alpha/PBSF in vitro. 1020 Mar 43

We have shown that metastasis is suppressed by low-dose total-body irradiation (TBI) in tumor-bearing rats. We have evaluated the immunological effects of low-dose TBI. Total-body irradiation with 0.2 Gy was given 14 days after the implantation of 5 x 10(5) allogenic hepatoma cells (KDH-8) which produce transforming growth factor beta (TGF-beta). On day 21, the splenocytes and tumor-tissue infiltrating lymphocytes were analyzed by FACScan and RT-PCR for the mRNA of the genes that encode tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), TGF-beta, interleukin (IL)-4, IL-10 and IL-6. The same procedure was conducted with untreated rats and with rats that underwent local irradiation with 0.2 Gy. The low-dose TBI significantly decreased the incidence of lung and lymph node metastasis (P < 0.01), whereas the same dose of local irradiation had no effect on the incidence of metastasis. The proportion of CD8+ cells in splenocytes increased in the low-dose TBI group (P < 0.01) compared to the locally irradiated and the untreated groups. The tumor-tissue infiltrating lymphocytes were also significantly increased after low-dose TBI (P < 0.01). The FACScan analysis revealed that 72% of the tumor-tissue infiltrating lymphocytes were CD8+. In both spleen and tumor tissue after low-dose TBI, mRNA expression of the genes that encode IFN-gamma and TNF-alpha increased, while that of the Tgfb gene decreased. There was no expression of the mRNAs of the Il4, Il6 and Il10 genes. CD8+ cells and the cytokine network may play an important role in the antitumor effect of low-dose TBI.
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PMID:The suppression of metastases and the change in host immune response after low-dose total-body irradiation in tumor-bearing rats. 1036 Jul 92

In the present study, we established an animal model for dengue virus infection using severe combined immunodeficient mice transplanted with a human hepatocarcinoma cell line (HepG2). At 7-8 weeks after transplantation, the HepG2-grafted mice were infected intraperitoneally with dengue virus type 2 (DEN-2). A higher titer of the virus was detected in the liver and serum but not in the brain in the early stage of postinfection. When the mice showed paralysis, the highest titer of virus was detected in the serum and brain. DEN-2 antigens were also found in HepG2 cells of the liver in the early stage and some neurons of the brain in the late stage. Upon clinical examination, thrombocytopenia, prolonged partial thromboplastin time, and increased hematocrit, blood urea nitrogen, and tumor necrosis factor alpha were seen in the paralyzed mice. Moreover, mild hemorrhage in the liver and tarry stool in the small intestine were observed in some mice. Our results show some similarities to human DEN infection and this mouse model might be valuable for studying some aspects of pathogenesis of this disease.
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PMID:Development of a novel mouse model for dengue virus infection. 1054 83

In the studies reported herein, we show that two complementary experimental models: inbred strains of mice (i.e. C57BL/6 and C3H/HeJ), and a differentiated line of rat hepatoma cells (i.e. L35 cells), require the activation of cytokines by monocyte/macrophages to display bile acid negative feedback repression of cholesterol 7alpha-hydroxylase (CYP7A1). Feeding a bile acid-containing atherogenic diet for 3 weeks to C57BL/6 mice led to a 70% reduction in the expression of hepatic CYP7A1 mRNA, whereas no reduction was observed in C3H/HeJ mice. The strain-specific response to repression of CYP7A1 paralleled the activation of hepatic cytokine expression. Studies using cultured THP-1 monocyte/macrophages showed that the hydrophobic bile acid chenodeoxycholate, a well established potent repressor of CYP7A1, induced the expression of mRNAs encoding interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFalpha). In contrast, the hydrophilic bile acid ursodeoxycholate, which does not repress CYP7A1, did not induce cytokine mRNA expression by THP-1 cells. Chenodeoxycholate activation of cytokines by THP-1 cells was blocked by the peroxisome proliferator-activated receptor gamma agonist rosiglitazone. The expression of cytokines (e.g. IL-1 and TNFalpha) by THP-1 cells paralleled with the ability of these cells to produce conditioned medium that when added to rat L35 hepatoma cells, repressed CYP7A1. Moreover, rosiglitazone, which blocks cytokine activation by macrophages, also blocked the repression of CYP7A1 normally exhibited by C57BL/6 mice fed the bile acid-containing atherogenic diet. The combined data indicate that the activation of cytokines may mediate CYP7A1 repression caused by feeding mice an atherogenic diet containing bile acids.
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PMID:Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7alpha-hydroxylase. 1082 15

The transcription factor nuclear factor kappaB (NFkappaB) is an essential antagonist of apoptosis during liver regeneration and embryonal development of hepatocytes. Several reports have indicated that NFkappaB may also inhibit the programmed cell death induced by cytokines, ionizing radiation, or cytotoxic drugs in some cancer cell lines. Because hepatocellular carcinomas (HCCs) are one of the most resistant tumors to systemic chemotherapy, we investigated the activation of NFkappaB and the consequence of its inhibition by an IkappaBalpha-super repressor during tumor necrosis factor alpha (TNFalpha)- and chemotherapy-induced apoptosis in HCC cell lines. We demonstrate that both TNFalpha and adriamycin activate NFkappaB in hepatoma cells. Activation of NFkappaB could be blocked through an adenoviral vector expressing the IkappaBalpha super repressor, regardless of the activating agent. Inhibition of NFkappaB enhanced the apoptosis induced by TNFalpha, whereas IkappaBalpha had an anti-apoptotic effect on chemotherapy-induced programmed cell death. A strong inhibition of chemotherapy- and TNFalpha-induced apoptosis by dominant-negative Fas-associated death domain indicated an essential contribution of death receptor-mediated apoptosis. To elucidate the different role of NFkappaB in chemotherapy-induced apoptosis, we investigated the expression of Fas (CD95) and Fas ligand (CD95 ligand), which have been described as important mediators of chemotherapy-induced cell death and as target genes of NFkappaB. However, our investigations demonstrated that in hepatoma cells, the chemotherapy-induced up-regulation of Fas (CD95) and Fas ligand (CD95 ligand) is not transcriptionally mediated through NFkappaB. Thus, other molecular mechanisms must account for the anti-apoptotic effect of IkappaBalpha in adriamycin-induced death of hepatoma cells. In summary, our investigations indicate that the activation of NFkappaB in response to cytotoxic drugs, in contrast to TNFalpha, exerts a pro-apoptotic stimulus rather than an anti-apoptotic function, which has implications for therapy of HCCs.
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PMID:IkappaBalpha gene therapy in tumor necrosis factor-alpha- and chemotherapy-mediated apoptosis of hepatocellular carcinomas. 1105 88

We have investigated the effects of arachidonic and palmitic acids in isolated rat liver mitochondria and in rat hepatoma MH1C1 cells. We show that both compounds induce the mitochondrial permeability transition (PT). At variance from palmitic acid, however, arachidonic acid causes a PT at concentrations that do not cause PT-independent depolarization or respiratory inhibition, suggesting a specific effect on the PT pore. When added to intact MH1C1 cells, arachidonic acid but not palmitic acid caused a mitochondrial PT in situ that was accompanied by cytochrome c release and rapidly followed by cell death. All these effects of arachidonic acid could be prevented by cyclosporin A but not by the phospholipase A(2) inhibitor aristolochic acid. In contrast, tumor necrosis factor alpha caused phospholipid hydrolysis, induction of the PT, cytochrome c release, and cell death that could be inhibited by both cyclosporin A and aristolochic acid. These findings suggest that arachidonic acid produced by cytosolic phospholipase A(2) may be a mediator of tumor necrosis factor alpha cytotoxicity in situ through induction of the mitochondrial PT.
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PMID:Arachidonic acid causes cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alpha aopototic signaling. 1113 37

Apoptosis, or programmed cell death, and the elimination of apoptotic cells are crucial factors in the maintenance of liver health Apoptosis allows hepatocytes to die without provoking a potentially harmful inflammatory response In contrast to necrosis, apoptosis is tightly controlled and regulated via several mechanisms, including Fas/Fas ligand interactions, the effects of cytokines such as tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta), and the influence of pro- and antiapoptotic mitochondria-associated proteins of the B-cell lymphoma-2 (Bcl-2) family. Efficient elimination of apoptotic cells in the liver relies on Kupffer cells and endothelial cells and is thought to be regulated by the expression of certain cell surface receptors. Liver disease is often associated with enhanced hepatocyte apoptosis, which is the case in viral and autoimmune hepatitis, cholestatic diseases, and metabolic disorders. Disruption of apoptosis is responsible for other diseases, for example, hepatocellular carcinoma. Use and abuse of certain drugs, especially alcohol, chemotherapeutic agents, and acetaminophen, have been associated with increased apoptosis and liver damage. Apoptosis also plays a role in transplantation-associated liver damage, both in ischemia/reperfusion injury and graft rejection. The role of apoptosis in various liver diseases and the mechanisms by which apoptosis occurs in the liver may provide insight into these diseases and suggest possible treatments.
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PMID:Apoptosis in diseases of the liver. 1134 18

Hepatitis B virus (HBV) gene expression is mainly regulated at the transcription initiation level. The viral X protein (pX) is a transcription coactivator/mediator targeting TFIIB for the recruitment of RNA polymerase II. Here we report a novel pX nuclear target designated HBXAP (hepatitis B virus X-associated protein). HBXAP is a novel cellular nuclear protein containing a PHD (plant homology domain) finger, a domain shared by many proteins that play roles in chromatin remodeling, transcription coactivation, and oncogenesis. pX physically interacts with HBXAP in vitro and in vivo via the HBXAP region containing the PHD finger. At the functional level HBXAP increases HBV transcription in a pX-dependent manner suggesting a role for this interaction in the virus life cycle. Interestingly, HBXAP collaborates with pX in coactivating the transcriptional activator NF-kappaB. Coactivation of NF-kappaB was also observed in tumor necrosis factor alpha-treated cells suggesting that pX-HBXAP functional collaboration localized downstream to the NF-kappaB nuclear import. Collectively our data suggest that pX recruits and potentiates a novel putative transcription coactivator to regulate NF-kappaB. The implication of pX-HBXAP interaction in the development of hepatocellular carcinoma is discussed.
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PMID:Hepatitis B virus pX interacts with HBXAP, a PHD finger protein to coactivate transcription. 1178 98

GP73 is a novel type II Golgi membrane protein of unknown function that is expressed in the hepatocytes of patients with adult giant-cell hepatitis (Gene 2000;249:53-65). Its expression pattern in human liver disease and the regulation of its expression in hepatocytes have not been systematically studied. The aims of the present study were to compare GP73 protein levels in viral and nonviral human liver disease and in normal livers, to identify its cellular sources, and to study the regulation of its expression in hepatoma cells in vitro. GP73 protein levels were quantitated in explant livers of patients with well-defined disease etiologies and compared with the levels in normal donor livers. GP73-expressing cells were identified immunohistochemically. GP73 expression in vitro was studied by Western blotting and immunofluorescence microscopy in HepG2 and SK-Hep-1 cells and in the HepG2-derived, hepatitis B virus (HBV)-transfected HepG2215 and HepG2T14.1 cell lines. Whole organ levels of GP73 were low in normal livers. Significant increases were found in liver disease due to viral causes (HBV, HCV) or nonviral causes (alcohol-induced liver disease, autoimmune hepatitis). In normal livers, GP73 was constitutively expressed by biliary epithelial cells but not by hepatocytes. Hepatocyte expression of GP73 was dramatically up-regulated in diseased livers, regardless of the etiology, whereas biliary epithelial cell expression did not change appreciably. GP73 was present at high levels in HepG2215 cells (a cell line that supports active HBV replication), but was absent in HepG2T14.1 cells (an HBV-transfected cell line that does not support HBV replication) and in HBV-free HepG2 cells. In SK-Hep-1 cells, GP73 expression was increased in response to interferon gamma (IFN-gamma), and inhibited by tumor necrosis factor alpha (TNF-alpha). In conclusion, increased expression of GP73 in hepatocytes appears to be a general feature of advanced liver disease, and may be regulated via distinct pathways that involve hepatotropic viruses or cytokines.
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PMID:Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease. 1202 28

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