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)

Tissue plasminogen activator (t-PA) levels in plasma or serum were studied in 416 patients with liver diseases: acute hepatitis (AH, n = 30); fulminant hepatitis (FH, n = 36); chronic inactive hepatitis (CIH, n = 57); chronic active hepatitis (CAH, n = 39); compensated liver cirrhosis (cLC, n = 78); decompensated liver cirrhosis (dLC, n = 84); hepatocellular carcinoma (HCC, n = 64); advanced hepatocellular carcinoma (aHCC, n = 28); and compared with that of a control group (n = 106) of healthy subjects. The t-PA levels showed significant increase in patients with AH, FH, CAH, cLC, dLC and HCC, compared with normal controls. The abnormal rates in t-PA levels (higher than 8.3 ng/ml) for each type of liver diseases were 86.1% in FH, 46.2% in CAH, 50% in cLC, 85.7% in dLC, 67.2% in HCC, and 89.3% in aHCC. t-PA levels tended to be higher in more advanced liver diseases. t-PA levels significantly correlated positively with plasminogen activator inhibitor (PAI-1) in AH, cLC, dLC, HCC and aHCC, and negatively with plasmin alpha 1-plasmin inhibitor complex (PIC), plasminogen (Plg), FDP, AT III and alpha 2-plasmin inhibitor (alpha 2-PI) in dLC, prothrombin time (PT) and fibrinogen (Fbg) in HCC. t-PA levels in patients with FH, CAH and dLC were significantly higher than those in patients with AH, CIH and cLC, respectively. Moreover, the changes of t-PA levels in the clinical courses of various liver diseases revealed that t-PA levels increased sensitively with progression of liver diseases or in advanced liver diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical evaluation of tissue plasminogen activator (t-PA) levels in patients with liver diseases. 131 84

The binding, internalization, and degradation of tissue-type plasminogen activator (t-PA) were studied in a rat hepatoma (Novikoff) cell line. Binding of t-PA to specific saturable high affinity binding sites (Kd = 12 nM, 54,000 sites/cell) was followed by internalization and degradation and did not require a functional active site. The catabolism of t-PA was not inhibited by an excess of urokinase-type plasminogen activator (u-PA), and t-PA bound to Novikoff membranes was not complexed to PAI-1, suggesting a mechanism independent of PAI-1. Additionally, a mannose receptor is not involved since t-PA binding was not influenced by an excess of mannose, galactose, ovalbumin, or EDTA. Furthermore, the degradation of t-PA was not influenced by 10 mM 6-aminohexanoic acid, a lysine analogue. The t-PA receptor binds to and can be eluted from wheat germ agglutinin-Sepharose. Cross-linking of t-PA with partially purified receptor and ligand blot analysis, suggest that t-PA binds to two proteins, a principal one of 55 kDa and a minor one of 43 kDa. Novikoff cells are able also to bind (Kd = 1.4 nM, 25,000 sites/cell) and degrade u-PA. The binding was inhibited by pro-u-PA and the amino-terminal fragment of u-PA, but not by an excess of t-PA. The u-PA receptor, but not the t-PA receptor, was removed by treatment with phosphatidylinositol-specific phospholipase C. Our results show that the clearance receptor for t-PA on Novikoff cells is different from the mannose receptor and the PAI-1-dependent receptor described in other cells. The rat hepatoma cells are thus a good model to study the PAI-1 independent hepatocyte-specific clearance of t-PA.
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PMID:Demonstration of a specific clearance receptor for tissue-type plasminogen activator on rat Novikoff hepatoma cells. 131 32

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic factors determining thrombosis and fibrinolysis. 134 88

The human hepatoma HuH-7 cell line was shown to constitutively express both a plasminogen activator (PA) and a plasminogen activator inhibitor (PAI). Four sublines of the HuH-7 cell line were analyzed and found to express differing amounts of both PA and PAI. The plasminogen activator produced by these cells was identified as urokinase based upon molecular weight, inhibition of activity with anti-UK but not anti-t-PA antibodies, adherence to an anti-UK affinity column and by Northern blotting demonstrating positive hybridization with the cDNA for UK, but not with the t-PA cDNA. The inhibitor produced by HuH-7 cells was identified as PAI-1 by molecular weight, immunoblotting techniques, adherence to an anti-PAI-1 affinity column, and by Northern blotting demonstrating positive hybridization with the cDNA for PAI-1, but not with the PAI-2 cDNA. The expression of both UK and PAI-1 by HuH-7 cells could be modulated by cytokines known to influence the acute phase response. The addition of interleukin-1 (IL-1) induced the expression of both UK and PAI-1. The increase of PAI-1 was due to an increase in amount of the PAI-1 mRNA. The presence of both interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) also increased UK and PAI-1 levels, although not as dramatically as IL-1. The addition of IL-1 together with IL-6 produced a slight synergistic response with respect to PAI-1 expression. This suggests that PAI-1 is able to respond to mediators which aid in the induction of the acute phase response. These studies demonstrate that cells of liver origin are able to produce components of the fibrinolytic system. The synthesis of these components can be altered by inflammatory mediators and thus may be involved in hepatic regulation of fibrinolysis in both normal and diseased states.
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PMID:Human HuH-7 hepatoma cells express urokinase and plasminogen activator inhibitor-1: identification, characterization and regulation by inflammatory mediators. 137 1

We studied the production of PAI-1 by human Hep G2 hepatoma cells. When culturing these cells in fresh medium (FM), PAI-1 accumulation rate was not linear: PAI-1 antigen after 24 h was 200 ng/10(6) cells while in subsequent 24 h periods, it was on average 1,000 ng/10(6) cells. Culture of Hep G2 cells in regular changes of a 12 h conditioned medium (CM) obtained from other Hep G2, instead of in FM, resulted in a 2-fold higher PAI-1 accumulation. In cells incubated in FM, PAI-1 mRNA declined rapidly after medium change and returned to basal levels after 24 h. In contrast, PAI-1 mRNA remained relatively stable when CM was used. The acute phase mediator interleukin 6 (IL-6) was not responsible for the autocrine stimulation of PAI-1: neither IL-6 nor antibodies to IL-6 altered the observed variations in PAI-1 expression. Our studies suggest the presence of an unknown PAI-1 stimulating factor.
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PMID:Constitutive plasminogen activator inhibitor 1 (PAI-1) biosynthesis in human Hep G2 hepatoma cells is maintained by an autocrine factor. 166 79

The acute phase behaviour of the fast inhibitor of tissue-type plasminogen activator (PAI-1) in vivo has been attributed to increased synthesis by endothelial cells. However, most other acute phase proteins in vivo are synthesized in the liver, which process is regulated by cytokines and can be studied in the hepatoma derived cell line HepG2. In this study, we investigated whether the synthesis of PAI-1 by HepG2 cells is regulated by the cytokines recombinant IL-1, rIL-6 and rTNF. Recombinant IL-1 and rTNF each increased PAI-1 synthesis by HepG2 cells two to three fold, whereas rIL-6 hardly had an effect. Mixtures of rIL-1, rIL-6 and rTNF increased PAI-1 synthesis up to eleven fold. The effects observed were not due to non-specific effects on HepG2 cell metabolism, since synthesis of alpha-2-antiplasmin was not effected by any of those cytokines, whereas fibrinogen synthesis was increased three to four fold by rIL-6, but was unaffected by rIL-1. Thus, our results demonstrate that synthesis of PAI-1 by HepG2 cells is regulated by cytokines and implicate that the acute phase behaviour of PAI-1 in vivo at least in part may be due to an increased synthesis by the liver.
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PMID:PAI-1 synthesis in the human hepatoma cell line HepG2 is increased by cytokines--evidence that the liver contributes to acute phase behaviour of PAI-1. 171 Dec 45

Liver cells are considered the principal source of plasma vitronectin. The human hepatoma cell line HepG2 produces vitronectin into its culture medium. In the current work we have analyzed the regulation of vitronectin by transforming growth factor-beta 1 (TGF beta 1) in this hepatoma cell line by Northern hybridization, polypeptide and immunoprecipitation analyses and compared the response to another TGF beta-regulated gene, plasminogen activator inhibitor (PAI-1). Rabbit antibodies raised against human plasma-derived vitronectin were used in immunodetection. Polypeptide and immunoprecipitation analyses of the medium and cells, as well as immunoblotting analysis of the cells and their extracellular matrices, indicated enhanced TGF beta 1-induced production and extracellular deposition of vitronectin. Accordingly, TGF beta 1 enhanced the expression of vitronectin mRNA at picomolar concentrations (2-20 ng/ml) as shown by Northern hybridization analysis. Comparison of the temporal TGF beta induction profiles of vitronectin and PAI-1 mRNAs showed that vitronectin was induced more slowly but the vitronectin mRNAs persisted longer. In addition, platelet-derived and epidermal growth factors had an effect on vitronectin expression, but it was of lower magnitude. TGF beta 1 enhanced the expression of PAI-1 but, unlike previous reports, epidermal growth factor did not have any notable effect on PAI-1 in these cells. The results indicate that TGF beta 1 is an efficient regulator of the production of vitronectin by HepG2 cells and that PAI-1 and vitronectin are not coordinately regulated. In addition, with affinity purified antibodies to vitronectin receptor, we observed strong enhancement of the alpha subunit of the receptor in response to TGF beta 1. These effects of TGF beta are probably involved in various processes of the liver where matrix induction and controlled pericellular proteolysis is needed, as in tissue repair.
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PMID:Enhancement of vitronectin expression in human HepG2 hepatoma cells by transforming growth factor-beta 1. 171 27

We have reported previously that incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone causes a 90% decrease in tissue-type plasminogen activator (tPA) activity secondary to a 4-fold increase in plasminogen activator inhibitor-1 (PAI-1) mRNA accumulation. Dexamethasone also induces a modest and transient increase in tPA mRNA. The cyclic nucleotide analog 8-bromo-cAMP (cA) causes a greater than 50-fold increase in PA activity, the result of a 90% decrease in PAI-1 and a sustained 2-fold increase in tPA mRNA accumulation. Dexamethasone and cA in combination cause a 150-fold increase in PA activity, the result of an 80% decrease in PAI-1 and a synergistic 15-fold increase in tPA mRNA. To determine the mechanism of this complex hormonal regulation, we have examined rates of synthesis and decay of PAI-1 and tPA mRNAs. Here we report that dexamethasone induces a 5-fold increase in PAI-1 gene transcription and does not significantly alter PAI-1 message decay; PAI-1 mRNA has a half-life of about 4 h in both untreated and dexamethasone-treated cells. In contrast, cA regulates PAI-1 mRNA by both decreasing the rate of PAI-1 gene transcription by 60% and accelerating the rate of PAI-1 message decay. Regulation of tPA by cA, both alone and in combination with dexamethasone, occurs primarily at the level of transcription. Dexamethasone and cA-induced tPA mRNA has a half-life of 2.75 h; tPA mRNA degradation is significantly inhibited by either cycloheximide or actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides. 173 71

Regulation of the human type 1 plasminogen activator inhibitor (PAI-1) promoter by transforming growth factor-beta (TGF beta) was studied. An 800-base pair fragment from the PAI-1 promoter and 5'-flanking region was fused to the firefly luciferase reporter gene and transfected into Hep3B human hepatoma cells. Treatment of the cells with TGF beta induced luciferase activity by more than 50-fold. Transfection studies using constructs with 5' or 3' deletions through this region revealed that two sequences were important in the TGF beta response. The first sequence was located in the proximal promoter (-49 to -87) and mediated an 11-fold induction with TGF beta, while the second more distal region (-636 to -740) contained two sequences which together mediated a 50-fold or greater response. Sequence comparison indicated that both of the responsive regions contained sequences with high homology to the AP-1 consensus binding site. Moreover, gel retardation analysis experiments demonstrated that both sequences bound a common nuclear protein, and that an oligonucleotide containing a consensus AP-1 sequence was able to compete for the binding of this common protein. Thus, the response of the PAI-1 gene to TGF beta is mediated by at least two separate regions, and both of these regions contain DNA sequences homologous to the AP-1 binding site.
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PMID:Identification of regulatory sequences in the type 1 plasminogen activator inhibitor gene responsive to transforming growth factor beta. 174 1

The binding of t-PA-PAI-1 to human hepatocytes at 4 degrees C reached a maximum at 2 h. Scatchard analysis indicated 74,000 +/- 11,000 high-affinity binding sites for complex per human hepatocyte, with a Kd of 0.87 +/- 0.09 nM. Almost identical results were achieved with the human hepatoma cell line Hep G2. Binding of [125I]t-PA-PAI-1 complex was unaffected by high concentrations of unlabelled t-PA, PAI-1, u-PA or u-PA-PAI-1 complex; only t-PA-PAI-1 complex competed for binding. Hepatocyte-bound t-PA-PAI-1 was internalized and degraded at 37 degrees C. Thus, hepatocytes have a specific t-PA-PAI-1 receptor that participates in clearance of this complex.
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PMID:The receptor for tissue plasminogen activator (t-PA) in complex with its inhibitor, PAI-1, on human hepatocytes. 184 16


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