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

Although treatment for hepatocellular carcinoma (HCC) has recently improved, most patients still relapse and die from this disease. The development of new therapeutic and preventive strategies for HCC is, therefore, required. A novel mutant protein (mutein) of human tumor necrosis factor alfa (TNF-alpha mutein F4614, 1SSSRGDSD... 29V ... 155L) was developed to decrease several adverse effects of TNF-alpha. F4614 is known to lack hypotensive effects of human TNF-alpha without losing its anti-tumor effect in mice transplanted with Meth-A sarcoma. Our study investigated the anti-tumor effects of F4614 against hepatoma cells in vitro and in vivo. F4614 significantly inhibited growth of all four tumor cells in vitro. A murine hepatoma cell line, MH134, when incubated in the presence of F4614, exhibited upregulation of surface major histocompatibility complex (MHC) class-I, intercellular adhesion molecule-1 (ICAM-1) and B7-1 molecules, and a decreased proportion of cells in the G2/M phase of the cell cycle. In addition, F4614 induced apoptosis in a significant number of MH134 cells. TNF-alpha and F4614 (5 microg/mouse daily for 5 days) showed similar anti-tumor activities in syngeneic MH134-bearing mice and heterogeneic PLC/PRF/5-bearing athymic nude mice. Intratumoral injection of F4614 or TNF-alpha was more effective than intravenous injection. Immunohistochemical analysis of the tumors treated by F4614 revealed that tumors were surrounded with a large number of Mac-1+ cells and a small number of CD4+ and CD8+ T cells; that suggests that intratumoral injection of F4614 elicited host immunoreactions. Thus, F4614 may be a new strategy for immunotherapy of HCC.
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PMID:A novel human tumor necrosis factor alfa mutein, F4614, inhibits in vitro and in vivo growth of murine and human hepatoma: implication for immunotherapy of human hepatocellular carcinoma. 965 97

Vascular endothelial growth factor (VEGF) is thought to take an important role in tumor angiogenesis. The present study examined VEGF expression immunohistochemically in hepatocellular carcinomas (HCCs) in various histological grades and sizes. In HCCs that were composed of cancerous tissues of single histological grade, VEGF expression was the highest in well-differentiated HCCs, followed by moderately differentiated HCCs, and then poorly differentiated HCCs. VEGF positivity gradually decreased with the increase in tumor size. In the nodules larger than 3.0 cm, 36.8% were VEGF-negative. In HCCs consisting of cancerous tissues of two different histological grades, the expression was less intensive in the higher-grade HCC component. VEGF was not expressed in sarcomatous areas, while VEGF was expressed in the surrounding HCC tissues. The expression was also remarkable in the noncancerous tissues in which inflammatory cell infiltration was apparent. VEGF expression was also examined in six HCC cell lines. In reverse-transcription polymerase chain reaction (RT-PCR) analysis, expressions of the two secretion types (VEGF121 and VEGF165) were the highest. Thus, VEGF protein in culture supernatant was measured by using enzyme-linked immunosorbent assay (ELISA) with or without inflammatory cytokines, i.e., interleukin (IL)-1beta, interferon (IFN)-alpha, IFN-gamma, and tumor necrosis factor (TNF)-alpha; and growth factors, i.e., epidermal growth factor (EGF), platelet-derived growth factor (PDGF)-BB, basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-alpha. As a result, secretion of VEGF from the cell lines was upregulated at various degrees. Based on these findings, VEGF expression in HCC tissues was thought to be related to the histological grade. The findings also indicate that various cytokines and growth factors could cooperatively act to enhance VEGF expressions in HCC.
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PMID:Expression of vascular endothelial growth factor in human hepatocellular carcinoma. 965 98

There is increased activity of the proinflammatory cytokine, tumor necrosis factor (TNF) in alcoholic liver disease (ALD). Hepatic neutrophil infiltration is a principal injurious manifestation of ALD. TNF can induce cellular oxidative injury directly, and indirectly by inducing neutrophil chemotactic factor (IL-8) production by hepatocytes. IL-8 activates and chemotactically attracts neutrophils to the liver where they release oxidizing substances. Patients with ALD also have decreased protective factors for cellular oxidative injury. Manganous superoxide dismutase (MnSOD) is an antioxidant protective factor. The objectives of these studies were to investigate mechanisms for induction of an injurious factor (IL-8) and a protective factor (MnSOD) in the HepG2 human hepatoma cell line. In the first set of experiments, IL-8 gene reporter constructs were used to transiently transfect a derivative (MVh2E1-9) of the HepG2 cell line which expresses P-4502E1 and metabolizes ethanol. Inactivation of the NF-kappaB and 3'NF-IL-6 DNA binding sites decreased IL-8 gene transcriptional activation in response to TNF while inactivation of the 5'NF-IL-6 binding site increased IL-8 gene transcriptional activity in response to TNF. This system may be useful to assess the effects of ethanol on TNF-induced hepatocyte IL-8 production. In the second set of experiments, HepG2 cells were cultured in 25 to 100 mmol concentrations of ethanol. Both TNF and ethanol increased HepG2 cell MnSOD activity in short-term (72 hr) cultures with ethanol. However, after long-term (10 weeks) culture with ethanol, there was no induction of MnSOD by ethanol and there was a diminished induction of MnSOD in response to TNF. Further studies are needed to assess the effect of this diminished induction of MnSOD with chronic ethanol culture on HepG2 cell susceptibility to TNF cytotoxicity. We conclude that transfected liver cell lines can be used to evaluate mechanisms for increased injurious factors and decreased protective factors in alcoholic liver injury.
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PMID:Use of transfected liver cells to evaluate potential mechanisms of alcohol-induced liver injury. 966 Feb 98

The activation of host defense mechanisms down-regulates microsomal cytochrome P450 in cell culture, humans, and animals. Investigation into various aspects of this effect using in vivo models has yet to define clearly the role that cytokines play in this phenomenon. The mechanism of down-regulation by immunostimulants, such as lipopolysaccharide (LPS), is explored with an in vitro model, utilizing a murine hepatoma (Hepa1) and a murine macrophage (IC-21) cell line. It is hypothesized that down-regulation of P450 activity by immunostimulants involves the activation of immune cells and the subsequent release of cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). The effects of immunostimulation on P450 activity are assessed by ethoxyresorufin O-dealkylase, an assay that measures CYP1A activity in Hepa1 cells. Initial studies demonstrated that LPS added directly to hepatoma cells had no effect on the levels of CYP1A1 activity. In contrast, a significant down-regulation in CYP1A1 activity occurred when hepatoma cells were incubated with monocyte conditioned medium obtained by incubating LPS with IC-21 cells. When pentoxifylline, a TNF-alpha synthesis inhibitor, was co-administered with LPS to macrophages, the down-regulation of CYP1A1 activity was prevented. The direct administration of murine recombinant TNF-alpha to hepatoma cells resulted in a down-regulation of CYP1A1 activity. These results implicated the release of TNF-alpha from macrophages as an important step in the down-regulation of CYP1A1 by LPS.
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PMID:Cytokine-mediated down-regulation of CYP1A1 in Hepa1 cells. 971 97

The plasma level of erythropoietin (Epo) in anemic patients suffering from inflammation is often low in relation to the blood hemoglobin concentration. Various proinflammatory cytokines have been tested for their action on the synthesis of Epo. Interleukin 1 (IL-1) and tumor necrosis factor-alpha(TNF-alpha) suppress Epo gene expression in isolated perfused rat kidneys and in human hepatoma cell cultures. IL-6 inhibits in the kidney, and conflicting results have been reported for its effect on Epo synthesis in hepatic cells. Several other cytokines tested were without effect. Thus, mainly IL-1 and TNF-alpha seem to be responsible for the defect in Epo production in severe systemic and renal inflammatory diseases.
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PMID:Proinflammatory cytokines lowering erythropoietin production. 972 35

Human hepatocytes infected by hepatitis B virus (HBV) produce the proinflammatory cytokine, tumor necrosis factor (TNF-). In this study, we explored the mechanism of induction of TNF- synthesis by HBV. We found that the stable HBV-transfected hepatoma cell line, 2. 2.15, expressed high-molecular-weight (HMW) TNF- mRNAs, which were absent in the parent HepG2 cells. Treatment of 2.2.15 cells with interferon alfa (IFN-) and/or interleukin-1beta (IL-1beta) reduced both viral gene transcription and TNF- mRNA expression. Transient or stable transfection of hepatocyte-derived cell lines with HBV X protein (HBx) expression vectors induced the production of biologically active TNF-. In these cells, the HBx-induced TNF- was detected both as cell-associated and soluble forms. Luciferase gene-expression assays showed that the TNF- gene promoter contained target sequences for HBx trans-activation within the proximal region of the promoter. These results indicate that the hepatocyte TNF- synthesis induced by HBV is transcriptionally up-regulated by HBx. Thus, HBx may have a role in the induction of the intrahepatic inflammatory processes that take place during acute and chronic hepatitis B.
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PMID:The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes. 975 38

The bioflavonoid silymarin is found to potently suppress both nuclear factor kappa-B (NF-kappaB)-DNA binding activity and its dependent gene expression induced by okadaic acid in the hepatoma cell line HepG2. Surprisingly, tumor necrosis factor-alpha-induced NF-kappaB activation was not affected by silymarin, thus demonstrating a pathway-dependent inhibition by silymarin. Many genes encoding the proteins of the hepatic acute phase response are under the control of the transcription factor NF-kappaB, a key regulator in the inflammatory and immune reactions. Thus, the inhibitory effect of silymarin on NF-kappaB activation could be involved in its hepatoprotective property.
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PMID:Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. 986 14

Little is known about the potential of immunomodulatory agents to lower tumor necrosis factor-alpha (TNF-alpha) synthesis in tissues of nonmonocytic origin. We studied effects of diverse drugs on the formation of immunoreactive TNF-alpha in the human hepatoma cell lines HepG2 and Hep3B, in which TNF-alpha production was induced by treatment (3 h incubation periods) with interleukin-1beta (IL-1beta, 300 pg/ml) or phorbol myristate acetate (PMA, 100 nmol/l). TNF-alpha production in IL-1beta-stimulated or PMA-stimulated hepatocyte cultures was not altered following the addition of dihydrocortisone (< or = 1 microg/ml), dibutyryl-cAMP (db-cAMP, < or = 100 micromol/l), adenosine (< or = 1 mmol/l), thalidomide (< or = 25 microg/ml), or cyclosporine (< or = 300 ng/ml). TNF-alpha production was inhibited by taurolidine (> or = 300 microg/ml), but this inhibition was associated with reduced cell viability. Pentoxifylline (1 mg/ml) did not influence PMA-induced TNF-alpha production, but it augmented IL-1beta-induced TNF-alpha production. Measurements of TNF-alpha mRNA by RT-PCR indicated that pentoxifylline exerted its effect posttranscriptionally. Additional studies with PMA-treated human whole blood cultures confirmed that pentoxifylline, db-cAMP, and adenosine reduced TNF-alpha production by leukocytes. These results provide first evidence to assume cell type-specific effects of immunomodulatory drugs on TFN-alpha synthesis, which may be relevant with respect to their clinical application.
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PMID:Tumor necrosis factor-alpha production by human hepatoma cell lines is resistant to drugs that are inhibitory to macrophages. 987 51

Responsiveness to cytokine-mediated acute inflammatory stimuli of the highly differentiated and polarized WIF-B hybrid cell line was studied by measuring the induction of alpha 1-acid glycoprotein and alpha 2-macroglobulin mRNAs after interleukin-1, interleukin-6 and tumor necrosis factor-alpha treatments in the presence of dexamethasone. Compared with their Fao parent, WIF-B cells were 10 times more responsive to 24-h interleukin-6 induction regarding alpha 2-macroglobulin induction. At variance from the response measured in Fao cells, the late effects of interleukin-6 treatment confirmed the higher sensitivity of WIF-B cells to this cytokine as a 72-h treatment as 10 times more effective than a 24-h treatment at inducting alpha 1-acid glycoprotein mRNA. These findings highlight the hepatocyte differentiation of WIF-B cells compared with other hepatoma cell lines, with respect to the regulation of acute-phase protein gene expression. They also make WIF-B cells a convenient model to study the molecular effects of interleukin-6 in terms of transduction and/or transcription, and the many cross-talks that occur during the regulation of acute-phase protein gene expression.
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PMID:Hepatocyte differentiation of WIF-B cells includes a high capacity of interleukin-6-mediated induction of alpha 1-acid glycoprotein and alpha 2-macroglobulin. 999 Feb 92

Postoperative infection is one of the main factors that affect mortality after hepatic resection, especially in patients with liver cirrhosis. In the pathogenesis of postoperative organ failures complicating endotoxemia or other surgical injuries, inflammatory cytokine has proved to play an important role. We herein report the changes in tumor necrosis factor-alpha, interleukin-1 beta, and granulocyte colony-stimulating factor in production from macrophages/monocytes stimulated with lipopolysaccharide (LPS) after hepatic resection of cirrhotic livers. Seven hepatocellular carcinoma patients with liver cirrhosis who were undergoing limited resection or segmental resection of the liver were examined. Peripheral blood monocytes were separated and incubated with 10 microg/ml LPS, and cytokine release was measured by ELISA before surgery as well as on Postoperative Days (PODs) 1, 3, 7, and 14. Preoperative cytokine production in cirrhotic patients was greater than cytokine production in noncirrhotic controls. Cytokine productivity increased after hepatic resection. TNF-alpha production was 1,846.6 +/- 882.6 pg/ml, 1,947.3 +/- 221.9 pg/ml, 2,486.9 +/- 519.7 pg/ml, and 1,640.2 +/- 416.0 pg/ml on PODs 1, 3, 7, and 14, respectively. The values on all PODs were significantly greater than the healthy control value, and the value on POD 7 was significantly greater than the preoperative value. Interleukin-1 beta and granulocyte colony-stimulating factor production values corroborated this result in general. In conclusion, macrophages/monocytes are primed in cirrhotic patients preoperatively, and they are supposed to carry greater cytokine producing abilities after hepatic resection. When endotoxin spills over in the blood or in the liver after hepatic resection, postoperative hepatic failure could develop as a result of hypercytokinemia.
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PMID:Inflammatory cytokine production enhancement in the presence of lipopolysaccharide after hepatic resection in cirrhotic patients. 1022 86


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