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)

Formation of the covalently stabilized complex of alpha 1-antitrypsin (alpha 1-AT) with neutrophil elastase, the archetype of serine proteinase inhibitor serpin-enzyme complexes, is associated with structural rearrangement of the alpha 1-AT molecule and hydrolysis of a reactive-site peptide bond. An approximately 4-kDa carboxyl-terminal cleavage fragment is generated. alpha 1-AT-elastase complexes are biologically active, possessing chemotactic activity and mediating increases in expression of the alpha 1-AT gene in human monocytes and macrophages. This suggested that structural rearrangement of the alpha 1-AT molecule, during formation of a complex with elastase, exposes a domain that is recognized by a specific cell surface receptor or receptors. To test this hypothesis, the known three-dimensional structure of alpha 1-AT and comparisons of the primary structures of the serpins were used to select a potentially exteriorly exposed and highly conserved region in the complexed form of alpha 1-AT as a candidate ligand (carboxyl-terminal fragment, amino acids 359-374). We show here that synthetic peptides based on the sequence of this region bind specifically and saturably to human hepatoma cells and human monocytes (Kd = 4.0 X 10(-8) M, 4.5 X 10(5) plasma membrane receptors per cell) and mediate increases in synthesis of alpha 1-AT. Binding of peptide 105Y (Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile) is blocked by alpha 1-AT-elastase complexes, antithrombin III (AT III)-thrombin complexes, alpha 1-antichymotrypsin (alpha 1-ACT)-cathepsin G complexes, and, to a lesser extent, complement component C1 inhibitor-C1s complexes, but not by the corresponding native proteins. Binding of peptide 105Y is also blocked by peptides with sequence corresponding to carboxy-terminal fragments of the serpins AT III and alpha 1-ACT, but not by peptides having the sequence of the extreme amino terminus of alpha 1-AT. The results also show that peptide 105Y inhibits binding of 125I-labeled alpha 1-AT-elastase complexes. Thus, these studies demonstrate an abundant, relatively high-affinity cell surface receptor which recognizes serpin-enzyme complexes (SEC receptor). This receptor is capable of modulating the production of at least one of the serpins, alpha 1-AT. Since the ligand specificity is similar to that previously described for in vivo clearance of serpin-enzyme complexes, the SEC receptor may also be involved in the clearance of certain serpin-enzyme complexes.
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PMID:Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. 216 76

Previous studies demonstrated that several cultured human tumor cell lines potentiate the conversion of prothrombin to thrombin by factor Xa and calcium in the absence of exogenous factor Va. In the present study, the specific binding of radioiodinated preparations of human factor X and factor Xa to a human hepatocellular carcinoma cell line (HepG2) that constitutively synthesizes a factor V/Va molecule, and a human bladder carcinoma cell line (J82) that does not synthesize factor V/Va, was examined. Radioiodinated factor Xa bound specifically to J82 and HepG2 cells, whereas no significant specific binding of 125I-factor X to either cell was observed. The binding isotherm of 125I-factor Xa to each tumor cell line exhibited a hyperbolic profile, and Scatchard analysis demonstrated a single class of binding site for factor Xa on each cell surface with Kd values of 1.66 +/- 0.39 and 1.64 +/- 0.52 nM and 566,000 +/- 71,000 and 28,000 +/- 6,000 binding sites/cell for HepG2 and J82 cells, respectively. Thrombin formation by cell-bound factor Xa was hyperbolic and saturable at 5 nM factor Xa on each cell line. Hanes-Woolf plots of the prothrombin activation data indicated that half-maximal rates of thrombin formation occurred at factor Xa concentrations of 1.50 +/- 0.43 nM and 1.42 +/- 0.48 nM on HepG2 and J82 cells, respectively. Pretreatment of J82 cells with polyclonal anti-human factor V IgG had no measurable effect on either the binding of 125I-factor Xa or prothrombin activation. However, pretreatment of HepG2 cells with anti-human factor V IgG inhibited prothrombin activation in a dose-dependent manner, but did not inhibit the binding of factor Xa to this cell. When both cell lines were preincubated with exogenous human factor Va, the binding of factor Xa to either HepG2 or J82 cells was marginally affected. These data indicate that HepG2 and J82 cells have cell surface factor Xa binding sites proximal to, but independent of, cell surface factor Va of either exogenous or endogenous origin.
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PMID:Binding of human factors X and Xa to HepG2 and J82 human tumor cell lines. Evidence that factor Xa binds to tumor cells independent of factor Va. 216 Sep 56

Previous work has shown that low-density lipoproteins (LDL) secreted by hepatoma-derived cell lines have an unusual composition compared to plasma LDL; rather than cholesteryl ester, the hepatoma cell-secreted LDL have a triacylglycerol core. We have found that they also have an increased negative charge, as judged by agarose electrophoresis. Since apolipoprotein B is a glycoprotein containing carbohydrate chains terminated with negatively charged sialic acid residues, we examined whether increased glycosylation of the apolipoprotein B from three hepatoma cell lines (Hep G2, Hep 3B and Huh 7) might account for the differences in LDL charge. The weight percent carbohydrate for Hep G2, Hep 3B and Huh 7 LDL-protein (1.1 +/- 0.2; 1.7 +/- 0.8; 0.4 +/- 0.1) was found to be extremely low compared with the 2.8-9% range we found for plasma LDL-protein, while the amount of LDL-lipid associated carbohydrate from hepatoma LDL was similar to that we found in plasma LDL. Furthermore, desialation of hepatoma cell-secreted LDL with neuraminidase did not normalize the negative charge to that of neuraminidase-treated plasma LDL. Western blots of thrombin proteolytic fragments indicated that, in addition to the T1-T4 fragments seen in plasma apolipoprotein B, apolipoprotein B of hepatoma-derived LDL produced four to five new fragments (T5-T9), suggesting increased exposure of proteolytic sites. Western blotting of the new fragments with antibodies specific for known apolipoprotein B sequences suggests that many of the new cleavage sites cluster in or near the putative LDL receptor recognition site.
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PMID:Unique structural properties of apolipoprotein B in low-density lipoproteins produced by several human hepatoma-derived cell lines. 217 71

Patients with liver disease frequently have hemostatic abnormalities which include accelerated fibrinolysis. In order to assess the fibrinolytic state in liver disease, plasma levels of fibrinogenolysis products (FgDP), fibrinolysis products (FbDP), and fibrinogenolysis plus fibrinolysis products (TDP) were measured with newly developed enzyme-linked immunosorbent assays based on monoclonal antibodies in 36 patients with liver disease (six patients with acute hepatitis, seven with chronic hepatitis, ten with liver cirrhosis, 11 with hepatocellular carcinoma, and two with intrahepatic cholestasis). As compared with healthy subjects, mean plasma levels of FbDP (1,083 +/- SD 1,254 vs. 236 +/- 100 ng/ml, P = 0.005) and TDP (1,773 +/- 1,814 vs. 669 +/- 212 ng/ml, P = 0.001) were significantly elevated in patients with liver disease, whereas FgDP was normal (389 +/- 202 vs. 396 +/- 132 ng/ml, P = 0.87). Plasma FbDP correlated very well with TDP (r = 0.986, P less than 0.00001) in liver disease. In addition, FbDP and TDP but not FgDP correlated with plasma concentrations of thrombin-antithrombin III complex. When plotted by the disease categories, the magnitude of elevations of FbDP and TDP was the most prominent in acute hepatitis followed by hepatocellular carcinoma. These findings indicate that activation of fibrinolysis occurs following thrombin generation, but increased primary fibrinogenolysis is rare in liver disease.
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PMID:Fibrinolysis and fibrinogenolysis in liver disease. 219 67

A new clotting method is described to assay des-gamma-carboxyprothrombin (DCP), using staphylocoagulase and adsorbed undiluted citrated plasma. The thrombin-coagulase formed was tested with a chromogenic substrate. The results were expressed in milliunits (m.u.). All 96 normal plasmas had less than 15 m.u. (mean 3.58 m.u.). Out of 56 non-hepatectomized cellular hepatocarcinomas, 40 had DCP levels between 20 and 420 m.u. (average between 40 and 60 m.u.); 71.4% of cellular hepatocarcinoma had an increased DCP and 90% were positive either in alpha-foetoprotein or in DCP. Ten cases of non-cellular hepatocarcinomas had normal DCP levels. We found no cases of cirrhosis or chronic hepatitis, whether active or persistent, with abnormal level of DCP. Out of 127 patients tested, no case was found with a high DCP and a low level of "total factor II", which could be interpreted as a vitamin K deficiency. Only one case of hepatocarcinoma had 25 m.u. of DCP and a low total factor II (20%) and 2 had less than 10% total factor II with no detectable DCP.
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PMID:Assay of des-gamma-carboxyprothrombin using staphylocoagulase. Application to the diagnosis of cellular hepatocarcinoma. 242 13

With the aim of improving the biological diagnosis of hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP) and factor V levels were assayed in 119 patients with HCC and 60 cirrhotic patients without HCC. Among the patients with HCC, increased levels of AFP (greater than 300 ng/ml) and of DCP (greater than 15 mU/ml) were observed in 36% and 69% of the cases, respectively. None of the 60 patients without HCC had increased AFP, and one had abnormal DCP; in this patient, DCP level returned to normal value after vitamin K1 injection. No significant correlation was found between increased AFP and DCP, thus indicating that the two tests complement each other for the diagnosis. A factor V level higher than expected from the reduced prothrombin time test of the patient was detected in 50% of patients with HCC and only 7% of those without HCC. No correlation was found between increased factor V and abnormal AFP or DCP. The thrombin time, fibrinogen activity to antigen ratio, and polymerization index failed to differentiate between cirrhosis and HCC. We conclude that AFP, DCP and factor V may give complementary informations in the diagnosis of HCC, one of these markers at least being positive in 88% of the patients.
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PMID:Coagulation assays as diagnostic markers of hepatocellular carcinoma. 246 2

Human S-protein (vitronectin) and hemopexin, two structurally related plasma proteins of similar molecular mass and abundance, were analyzed for tyrosine sulfation. Both proteins were synthesized and secreted by the human hepatoma-derived cell line Hep G2, as shown by immunoprecipitation from the culture medium of [35S]methionine-labelled cells. When Hep G2 cells were labelled with [35S]sulfate, S-protein, but not hemopexin, was found to be sulfated. Half of the [35S]sulfate incorporated into S-protein was recovered as tyrosine sulfate. The stoichiometry of tyrosine sulfation was approximately two mol tyrosine sulfate/mol S-protein. Examination of the S-protein sequence for the presence of the known consensus features for tyrosine sulfation revealed three potential sulfation sites at positions 56, 59 and 401. Tyrosine 56 is the most probable site for stoichiometric sulfation, followed by tyrosine 59 which appears more likely to become sulfated than tyrosine 401. Tyrosines 56 and 59 are located in the anionic region of S-protein which has no homologous counterpart in hemopexin. We discuss the possibility that tyrosine sulfation of the anionic region of S-protein may stabilize the conformation of S-protein in the absence of thrombin-antithrombin III complexes and may play a role in its binding to thrombin-antithrombin III complexes during coagulation.
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PMID:Sulfation of two tyrosine-residues in human complement S-protein (vitronectin). 247 56

Patients with liver disease frequently have multiple hemostatic abnormalities. Coagulation and fibrinolytic factors and inhibitors may decrease as the result of impaired synthesis and/or enhanced catabolism. In order to assess the actual degree of activation of coagulation and fibrinolytic systems in liver disease, plasma levels of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) were measured together with cross-linked fibrin derivatives (XDP), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI-1) in 31 patients with liver disease (five patients with acute hepatitis, seven with chronic hepatitis, nine with liver cirrhosis, and ten with hepatocellular carcinoma). Mean plasma levels of TAT (mean 4.2 +/- SD 4.0 micrograms/L), PAP (0.7 +/- 0.7 mg/L), and XDP (374 +/- 518 micrograms/L) were significantly elevated in patients with liver disease as compared with normal subjects (TAT of 1.7 +/- 0.3 micrograms/L, PAP of 0.2 +/- 0.1 mg/L, and XDP of 30 +/- 14 micrograms/L; P less than 0.005). Plasma concentrations of t-PA and PAI-1 antigens were also elevated. When plotted by the disease categories, the magnitude of elevations of these parameters was variable among subgroups. Patients with acute hepatitis had considerably higher TAT levels. The mean PAP values were relatively high in chronic hepatitis and hepatocellular carcinoma, in which an elevation of the t-PA/PAI-1 ratio was observed. Although clearance of TAT and PAP should be evaluated in the future, these findings suggest that excessive amounts of thrombin and plasmin are actually generated in patients with liver disease.
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PMID:Thrombin and plasmin generation in patients with liver disease. 252 2

Immunoreactive endothelin (ET) and big-endothelin (big-ET) in conditioned media of endothelial and of non-endothelial cells were studied using sandwich-type enzyme immunoassays. Immunoreactivities of both ETs were detected in the media of all four endothelial cells tested. Among non-endothelial cells, tumor cell lines with epithelial-like morphology also produced immunoreactive ET and/or big-ET, although the total amount of ETs was one or two orders of magnitude less than that produced by PAE (porcine aortic endothelial cells). Immunoreactive ETs produced by HepG-2 (human hepatocellular carcinoma) and some other cells were characterized by gel-filtration HPLC and reverse-phase HPLC. These studies revealed the production of ET-1 and human big-ET-1 by these cells, although the immunoreactive ETs produced by the tumor cells were more heterogeneous than those produced by endothelial cells. The regulatory effects of thrombin and transforming growth factor-beta (TGF-beta) on the production of ETs were investigated. TGF-beta markedly stimulated the production of both ETs in HepG-2 and slightly decreased the big-ET level in A549 (human lung carcinoma). HPLC analysis showed that the major immunoreactive ETs induced by TGF-beta in HepG-2 were identical to ET-1 and human big-ET-1. These results demonstrated that production of ET-1 and big-ET-1 was not restricted to endothelial cells and was induced by TGF-beta in HepG-2 at the same levels as those produced by PAE.
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PMID:Production of endothelin-1 and big-endothelin-1 by tumor cells with epithelial-like morphology. 269 51

We studied the effects on platelet function of cells isolated from freshly dissociated human tumor tissues (11 breast carcinomas, 9 colon carcinomas and 1 lymph node metastasis from melanoma) obtained at surgery as compared with cultured human tumor cells: namely, human melanoma 1402 cell line derived from a primary tumor and two lines derived from lymph node metastases (ME 7110/2 and Me 665/1) as well as a human hepatoma cell line (Hep G2). The three melanoma cell lines activated platelets by producing ADP, as evidenced by the inhibitory effect of apyrase and by the direct measurement of the agonist in the supernatants of tumor cell suspensions; this production was much greater by the cells derived from metastases than by the cells derived from the primary tumor. On the other hand, aggregation induced by Hep G2 hepatoma cells was unaffected by apyrase and was inhibited by hirudin or concanavalin A, suggesting that the cells aggregate platelets by producing thrombin, probably through tissue factor activity of the cells themselves. Cells isolated from 16 of the 21 human tumor tissues possessed a potent platelet-aggregating effect, which was not inhibited by apyrase, hirudin or concanavalin A, but was virtually abolished by the cysteine protease inhibitors iodoacetic acid or p-hydroxymercuri-phenylsulfonate. Collectively, our data demonstrate that cells isolated from freshly dissociated tumor tissues activate platelets through tumor-associated cysteine proteinases rather than by the ADP- or thrombin-dependent mechanisms characteristic of cultured human tumor cell lines.
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PMID:Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues. 276 27


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