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)

The serum concentration of the inter-alpha trypsin inhibitor heavy chain 4 protein (ITIH4) increases (from 1.4-3 times) in male patients suffering of different acute-phase processes (myocardial infarction, unstable angina or programmed surgery). The concentration of C-reactive protein (CRP) in these samples ranged from 15 microg/ml to 133 microg/ml. Using the hepatocarcinoma HepG2 cell line we have observed up-regulation of ITIH4 mRNA expression upon dose-response treatments with interleukin-6 (IL-6). This effect correlates with the increase of radiolabeled ITIH4 in the cellular media of (35)S-labeled HepG2 cells treated with the cytokine. A similar effect was observed for haptoglobin mRNA, used as a control for acute-phase protein expression. IL-1beta, although up-regulating the expression of alpha(1)-acid glycoprotein in these cells, did not induce any effect in the expression of ITIH4. No changes were observed after TNF-alpha treatments. The results presented here indicate that ITIH4 is a type II acute-phase protein in humans.
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PMID:ITIH4 serum concentration increases during acute-phase processes in human patients and is up-regulated by interleukin-6 in hepatocarcinoma HepG2 cells. 1048 81

CD40, a member of the tumor necrosis factor receptor (TNFR) family, plays a crucial role in the survival, proliferation, and differentiation in B cells. However, the expression of CD40 other than in B cells has not been well studied. Therefore, we investigated the expression and function of CD40 in hepatocellular carcinomas (HCCs). Expression of CD40 mRNA in 6 established HCC cell lines was analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and CD40 expression on cell surface was examined by flow cytometrical analysis. We also examined the expression of CD40 in human HCC tissues (45 cases) and nontumor liver tissues (30 cases) by immunohistochemistry. To examine the function of CD40 in HCC cells, we investigated the effect of CD40 signaling on anti-Fas antibody and TNF-alpha-induced apoptosis in HepG2 cells. In addition, intracellular levels of cysteine protease P32 (CPP32) protein in HepG2 cells were also determined by Western blotting. We have shown that 6 HCC cell lines constitutively expressed CD40 mRNA and membrane-bound CD40 antigen, which was slightly up-regulated by interferon gamma (IFN-gamma). In addition, 60% of human HCC tissues demonstrated positive staining for CD40, whereas nontumor tissues showed little detectable staining. In HepG2 cells, CD40 stimulation does not affect cell viability, but significantly inhibited Fas and TNFR-mediated apoptosis in a dose-dependent manner by blocking the activation of CPP32. From these results, we conclude that CD40 expression in HCCs plays an important role in tumor biology, especially the resistance against Fas and TNFR-mediated apoptosis.
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PMID:Expression of functional CD40 in human hepatocellular carcinoma. 1049 43

Tumor necrosis factor (TNF)-alpha is a potent inducer of apoptotic cell death in various tissues, whereas the transcription factor nuclear factor (NF)-kappaB is essential to protect against TNF-alpha-induced apoptosis. Human hepatoma cell lines were used to investigate the effectiveness and specificity of the fungal metabolite gliotoxin in inhibiting TNF-alpha-induced NF-kappaB activation in transformed cells. Gliotoxin-TNF-alpha cotreatment induced massive apoptosis in these otherwise TNF-alpha-resistant cell lines. With the use of the mouse partial hepatectomy model, we were also able to demonstrate in vivo the capacity of gliotoxin to act as inhibitor of NF-kappaB activation. Bromodeoxyuridine staining of liver sections showed that the lack of NF-kappaB activation correlated with 80% reduction of DNA synthesis 48 h after hepatectomy compared with untreated controls. Additionally, animals treated with gliotoxin showed nuclear condensation and DNA laddering of hepatocytes indicative of apoptosis 24 h after hepatectomy. In summary, our results demonstrate that NF-kappaB is essential in defining the fate of liver cells in response to TNF-alpha in vivo and furthermore implicate gliotoxin as a potential new response modifier for TNF-alpha-based therapy.
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PMID:NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration. 1064 76

The concentration of circulating thrombopoietin (TPO) is relatively high in patients with thrombocytosis reactive to inflammatory diseases. We investigated whether immunomodulatory cytokines stimulate TPO synthesis in cultured human hepatoma cells (lines HepG2 and Hep3B), renal proximal tubular cells, and bone marrow fibroblasts. The effects of interleukins (IL) IL-1beta, IL-6, and IL-11 and of tumor necrosis factor-a (TNF-alpha) on the rate of TPO secretion were measured by ELISA. TPO mRNA levels were quantitated by competitive reverse transcription PCR. HepG2 and Hep3B cells produced significant amounts of TPO mRNA and TPO protein. Renal tubular cells synthesized less TPO, and in bone marrow fibroblasts, neither TPO mRNA nor TPO protein was detected. Only IL-6 affected TPO protein secretion, causing a 1.5-fold stimulation in HepG2 and Hep3B cells in 24-h incubation periods. The TPO mRNA content in these cells was doubled by IL-6 after 2, 6, or 24 h of stimulation. Thus, IL-6 could cause thrombocytosis in inflammatory disease partly by increasing hepatic TPO production.
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PMID:Interleukin-6 increases thrombopoietin production in human hepatoma cells HepG2 and Hep3B. 1084 Oct 78

In this study, we examined the susceptibility of murine hepatoma Hepa1-6 cells to undergo IFN-gamma- and/or TNF-alpha-induced apoptosis. IFN-gamma or TNF-alpha alone had no demonstrable cytotoxic effects, whereas IFN-gamma and TNF-alpha in combination induced apoptosis drastically in Hepa1-6 cells. During this apoptosis, an increase in caspase-3- and -8-like protease activities and activation of caspase-3, identified by the appearance of its p17 fragment, were observed. Moreover, the cytotoxic induction and caspase-3 activation were effectively inhibited by Z-Asp-CH(2)-DCB (Z-Asp), a caspase inhibitor. Further, an elevation of cytochrome c in the cytosol, in a parallel to activation of caspase-3, was observed in a time-dependent manner. Concurrently, up-regulation of caspase-11 gene expression and processing of procaspase-11 were detected during this apoptosis. These results suggest that the caspase-3 activation, the release of cytochrome c from mitochondria, and increased caspase-11 gene expression involve in synergistic induction of apoptosis in Hepa1-6 cells by IFN-gamma and TNF-alpha.
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PMID:Synergistic induction of apoptosis in murine hepatoma Hepa1-6 cells by IFN-gamma and TNF-alpha. 1086 Aug 13

Hepatitis C virus (HCV) often causes a prolonged and persistent infection which may lead to hepatocellular carcinoma. We have previously reported that the nonstructural 5A (NS5A) protein of HCV promotes cell growth [Ghosh, A.K., Steele, R., Meyer, K., Ray, R., Ray, R.B., 1999. Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. J. Gen. Virol. 80, 1179-1183]. In this study, we investigated the role of HCV NS5A (genotype 1a, strain H) in TNF-alpha induced apoptotic cell death. HepG2 cells expressing NS5A exhibited an inhibitory role in relation to TNF-alpha mediated apoptotic cell death. The NS5A protein blocked the activation of caspase-3 and inhibited proteolytic cleavage of the death substrate poly (ADP-ribose) polymerase in TNF-alpha induced cells. Together, these results suggest that HCV NS5A protein protects against TNF-alpha mediated apoptotic cell death.
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PMID:Hepatitis C virus NS5A protein protects against TNF-alpha mediated apoptotic cell death. 1086 96

Baculovirus transfection strategies have proven successful at transferring foreign DNA into hepatoma cells and primary hepatocytes. When testing the utility of these methodologies in cultured hepatocytes, we discovered that the presence of baculovirus disrupts the phenobarbital (PB) gene induction process, a potent transcriptional activation event characteristic of highly differentiated hepatocytes, and repressed expression of the albumin gene. In concert with previous reports from our laboratory demonstrating that increased cAMP levels can completely repress the induction of specific cytochrome P450 (CYP) genes, cAMP concentrations and PKA activities were measured in the primary hepatocytes subsequent to baculovirus exposure. However, neither parameter was affected by the presence of the virus. To evaluate whether immune response modulation was triggered by baculovirus exposure, RNase protection assays were performed and demonstrated that baculovirus infection activates TNF-alpha, IL-1alpha and IL-1beta expression in the primary hepatocyte cultures. Immunocytochemical experiments indicated that the production of cytokines was likely due to the presence of small numbers of Kupffer cells present in the culture populations. Exogenously added TNF-alpha was also effective in repressing PB induction, consistent with other reports indicating that inflammatory cytokines are capable of suppressing expression of biotransformation enzyme systems. Comparative studies demonstrated the specificity of these effects since exposures of hepatocytes to adenoviral vectors did not result in down-regulation of hepatic gene responsiveness. These results indicate that baculovirus vectors enhance the expression of inflammatory cytokines in primary hepatocyte cultures, raising concerns as to whether these properties will compromise the use of baculovirus vectors for study of cytochrome P450 gene regulation, as well as for liver-directed gene therapy in humans.
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PMID:Baculovirus vectors repress phenobarbital-mediated gene induction and stimulate cytokine expression in primary cultures of rat hepatocytes. 1091 98

Aflatoxin B1 (AFB1) induced mutation of the p53 gene at codon 249 (p53mt249) is critical during the formation of hepatocellular carcinoma (HCC) following hepatitis B virus (HBV) infection. p53mt249 markedly increases insulin-like growth factor II (IGF-II) transcription largely from promoter 4, accumulating the fetal form of IGF-II. Modulation of the transcription factor binding to IGF-II P4 by wild-type p53 and p53mt249 was identified. Wild-type p53 inhibited binding of transcription factors Sp1 and TBP on the P4 promoter, while p53mt249 enhanced the formation of transcriptional complexes through enhanced DNA-protein (Sp1 or TBP) and protein-protein (Sp1 and TBP) interactions. p53mt249 stimulates transcription factor Sp1 phosphorylation which might be a cause of increased transcription factor binding on the P4 promoter while wild-type p53 does not. Transfection of hepatocytes with p53mt249 impaired induction of apoptosis by the HBV-X protein and TNF-alpha. Therefore, the blocking of apoptosis through enhanced production of IGF-II should provide a favorable opportunity for the selection of transformed hepatocytes. These results explain the molecular basis for the genesis of HCC by p53mt249 which was found to be induced by a potent mutagen, AFB1.
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PMID:Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma. 1094 25

Little is known as to how hepatectomy is associated with the growth of hepatic tumours, which may reside in the remaining liver after curative resection for hepatocellular carcinoma. Using an intra-hepatic tumour implantation model in rats, the effects of hepatectomy on tumour growth in the remaining liver were investigated. On post-operative day 7, the tumour weight in the remaining liver following 30% hepatectomy was 0.321+/-0.058 g (mean +/- SD) which was significantly greater than that (0.245+/-0.040 g) in sham operations (P<0.05). However, the tumour weight (0.156+/-0.067 g) in the remaining liver following 60% hepatectomy was significantly lower than that in sham animals (P< 0.005). The number of TdT-mediated dUTP nick-end labelling (TUNEL) positive tumour cells was significantly increased in 60% hepatectomy as compared with the sham and 30% hepatectomy group. The mRNA expression of TGF-beta1, TNF-alpha and Fas in the tumour portion of 60% hepatectomy, was higher than that in 30% hepatectomy group. Plasma levels of TGF-beta1 were inversely correlated with intra-hepatic tumour weights. These results suggest that major hepatic resection may lead to an increased induction of apoptosis for the remaining hepatic tumour.
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PMID:Major hepatic resection may suppress the growth of tumours remaining in the residual liver. 1099 59

Syndecan-1 and syndecan-2-two cell surface heparan sulfate proteoglycans-were described in normal human liver. Proteoglycans can modulate the effect of cytokines, and cytokines can influence the expression of proteoglycans. In the present work the regulatory effect of IL-1beta, IL-6, TNF-alpha, IFN-gamma and TGF-beta1 on syndecan-1 and syndecan-2 expression of hepatocytes, hepatoma cell lines, liver and skin fibroblasts has been studied. All cytokines were able to influence the steady state level of syndecan-1 and syndecan-2 mRNA. Their action was target cell specific resulting in either up- or downregulation except TGF-beta1 that was stimulatory in all cell types examined.
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PMID:Cytokine regulation of syndecan expression in cells of liver origin. 1102 73


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