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

Dexamethasone induces an inhibitor of plasminogen-dependent fibrinolysis in rat hepatoma (HTC) cells. The specificity of the inhibitor for urokinase and plasmin was investigated using both fibrinolytic and esterolytic assays. Urokinase, but not plasmin, was inhibited by serum-free conditioned medium from cells incubated with 0.1 microM dexamethasone. The specificity of the inhibitor for plasminogen activator was demonstrated directly by the inhibition of the urokinase-catalyzed activation of 125I-plasminogen to 125I-plasmin. The inhibitory activity was stable to pH 3 for 2 h at 37 degrees C, a condition which inactivated fibrinolytic inhibitors in serum, suggesting a cellular origin for the inhibitor. Further evidence for the cellular origin was the constant daily production of inhibitor throughout a 4-day incubation with dexamethasone in serum-free medium. SF HTC-H1 cells, selected for their ability to grow in serum-free medium (Thompson, E. B., Anderson, C. U., and Lippman, M. E. (1975) J. Cell Physiol. 86, 403-412), were grown for 76 days (at least 30 generations) in the presence or absence of serum; dexamethasone induced equivalent amounts of inhibitory activity in cells which had been grown under both conditions. We conclude that the dexamethasone-induced inhibitor from HTC cells is a cellular product which is specific for the inhibition of plasminogen activation and which differs from other reported fibrinolytic inhibitors.
 ...
PMID:The dexamethasone-induced inhibitor of fibrinolytic activity in hepatoma cells. A cellular product which specifically inhibits plasminogen activation. 646 54

The adherent human hepatoma cell line Hep G2 exhibits receptor mediated endocytosis and catabolism of tissue-type plasminogen activator.plasminogen activator inhibitor type-1 (t-PA.PAI-1) complexes formed when exogenous t-PA combines with endogenous PAI-1 in the extracellular matrix. To determine whether the other major PA, urokinase (u-PA), which also complexes with PAI-1, is metabolised via the same mechanism, 125I-labelled high (hmw) and low (lmw) molecular weight forms of u-PA were incubated with Hep G2 cells at 4 degrees C for 2 hr in the absence and presence of a 100-fold excess of unlabelled ligand in order to detect specific binding. Both hmw and lmw 125I-u-PA formed complexes with PAI-1 and these bound specifically and with high affinity (apparent Kd 3.9 and 4.1 nM, with Bmax 78 x 10(3) and 83 x 10(3) binding sites/cell respectively). Binding by each form of radiolabelled u-PA was inhibited in a dose-dependent fashion by unlabelled t-PA, hmw-u-PA, lmw-u-PA, and by monoclonal anti-PAI-1 antibody. At 37 degrees C, bound hmw and lmw 125I-u-PA.PAI-1 complexes were internalised and degraded rapidly. These findings indicate that the specificity of the previously described receptor which mediates PAI-1 dependent catabolism of t-PA by Hep G2 cells extends to complexes of u-PA with this inhibitor.
 ...
PMID:Urokinase binding and catabolism by Hep G2 cells is plasminogen activator inhibitor-1 dependent, analogous to interactions of tissue-type plasminogen activator with these cells. 748 38

HGF is a powerful mitogen for both rat and human hepatocytes, epithelial cells and endothelial cells in vitro, and is angiogenic in vivo. It has considerable homology with plasminogen and has been shown to upregulate urokinase-type plasminogen activator (u-PA) in endothelial cells as well as u-PA and its receptor in kidney epithelial cells. In this study, we report that human recombinant HGF stimulates expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue factor (TF) in the human hepatoma cell line HepG2. PAI-1 antigen as determined by a specific enzyme-linked immunosorbent assay increased up to threefold in conditioned media of HepG2. This increase was dose dependent with maximum stimulation achieved with a concentration of 50 ng/mL of hepatocyte growth factor (HGF). PAI-1 antigen also increased up to fourfold in the extracellular matrix in HGF treated HepG2. The production of the PAI-1 binding protein vitronectin (Vn) was not affected by HGF. In contrast, TF activity in HepG2 treated with HGF increased up to twofold. As determined by Northern blotting, PAI-1 and TF-specific mRNA were increased significantly in the presence of HGF, whereas Vn mRNA was not affected. The increase in PAI-1 and TF mRNA was also seen when HepG2 were incubated with HGF in the presence of cycloheximide, thereby indicating that de novo protein synthesis is not required to mediate the effect. u-PA could be detected neither in unstimulated or HGF-stimulated HepG2 cells on the antigen level nor on the mRNA level. In conclusion, our data give evidence that HGF, in addition to its proliferative effect for different cell types, is also involved in the local regulation of fibrinolysis and coagulation. One could speculate that HGF might modulate processes requiring matrix degradation by increasing the expression of the protease u-PA in one cell type and by upregulating the expression of the serine protease inhibitor PAI-1 in a different cell type. Because u-PA has been shown to activate latent HGF to the active form, it could furthermore be speculated that by upregulating PAI-1, which in turn could inhibit u-PA, HGF might regulate its own activation.
 ...
PMID:Hepatocyte growth factor stimulates expression of plasminogen activator inhibitor type 1 and tissue factor in HepG2 cells. 751 5

We measured urokinase-type plasminogen activator (u-PA) plasma levels in patients with various chronic liver diseases, including hepatocellular carcinoma (HCC), also measuring these levels in healthy volunteers. Plasma u-PA levels in the group of patients with decompensated liver cirrhosis (mean modified Pugh score of 14 points) were markedly elevated and significantly higher than those in the patients with decompensated liver cirrhosis with HCC (modified Pugh score of 10 points), those with compensated liver cirrhosis with HCC, and those with compensated liver cirrhosis. Patients in all these three latter groups had moderately and significantly elevated u-PA levels compared to levels in the chronic hepatitis group and the healthy volunteers, but the levels were not significantly different from each other. There was no relationship between u-PA plasma level and the type of HCC tumor invasion or number or size of tumors. Significant correlations were found between u-PA plasma levels and the results of seven different liver function tests in three groups without associated HCC; u-PA antigen and prothrombin time (%), hepaplastin test (%), serum cholinesterase, serum albumin, serum total cholesterol, and indocyanine green clearance correlated negatively, while u-PA antigen and serum total bilirubin correlated positively. These results suggest that plasma u-PA is associated with deterioration of liver function but not with HCC invasion.
 ...
PMID:Elevated urokinase-type plasminogen activator plasma levels are associated with deterioration of liver function but not with hepatocellular carcinoma. 787 70

The glycoprotein tissue-type plasminogen activator (t-PA) is subject to hepatic clearance in humans. Here, the interaction of t-PA with a well-differentiated hepatoma cell line (HepG2) was examined. Suspended HepG2 cells bound 125I-t-PA in a specific, saturable, and reversible fashion through a Ca(2+)-dependent, active site-independent mechanism. Binding isotherms indicated a high affinity system with a single class of saturable binding sites (Kd 39 nM; maximum binding capacity 493,000 sites per cell). Bound t-PA was rapidly degraded at 37 degrees C in a manner inhibited by lysosomotropic agents or metabolic inhibitors. Pretreatment of t-PA with monoclonal antibodies against the EGF/fibronectin finger domain, but not kringle 2 or kringle 1, reduced total binding by 86%. Binding of 125I-t-PA to HepG2 cells was inhibited by monosaccharides fucose and galactose and by the neoglycoprotein fucosyl-albumin. Enzymatic removal of alpha-fucose residues, but not alpha-galactose, high mannose, or complex oligosaccharide from 125I-t-PA, reduced specific binding by 60 +/- 5%. Binding was also inhibited by high, but not low, molecular weight urokinase, which contains an EGF-based threonine-linked alpha-fucose homologous to that of t-PA. These data suggest that EGF-associated O-linked alpha-fucose may mediate t-PA binding and degradation by HepG2 cells. This mechanism may be relevant to other proteins with analogous structures.
 ...
PMID:alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells. 811 82

The role of plasminogen activator inhibitor type 1 (PAI-1) in the clearance of tissue-type plasminogen activator (t-PA) by hepatocyte-like cells was studied. Rat (Novikoff) hepatoma cells were able to bind and degrade t-PA in a PAI-1 independent fashion, but PAI-1 markedly increased the rate of degradation and t-PA/PAI-1 was a more efficient inhibitor of 125I-t-PA or of 125I-t-PA/PAI-1 degradation than free t-PA. Competition studies revealed that the effect of PAI-1 is unlikely to involve determinants located on the PAI-1 part of the complex: 1) an excess of free PAI had no effect on the rate of degradation of 125I-t-PA/PAI-1.2) Complexes of PAI-1 with urokinase-type PA or with a t-PA mutant lacking the finger and growth factor domains were unable to compete for the binding and degradation of free or PAI-1-complexed 125I-t-PA.3) t-PA KHRR296-299AAAA, a mutant which reacts 2 orders of magnitude slower with PAI-1 than wild type t-PA, behaved similar to wild type t-PA. The clearance via both the PAI-1-dependent and the PAI-1-independent mechanisms was inhibited by the receptor-associated protein, a general inhibitor of clearance mediated by the LDL receptor-related protein. We conclude that t-PA can be cleared by rat hepatoma cells in a PAI-1 independent fashion, but after complex formation with PAI-1, binding of t-PA to the cells is increased and clearance accelerated. Both mechanisms seem to involve the same receptor.
 ...
PMID:The role of plasminogen activator inhibitor type 1 in the clearance of tissue-type plasminogen activator by rat hepatoma cells. 811 17

Type 1 plasminogen activator inhibitor (PAI-1) is the major physiological inhibitor of plasminogen activation, inhibiting both tissue- and urokinase-type plasminogen activators. In HTC rat hepatoma cells, glucocorticoids increase PAI-1 activity, antigen and mRNA accumulation 3- to 5-fold; this increase is due solely to an increase in the rate of PAI-1 gene transcription. We have identified the cis-acting sequences in the 5'-flanking sequence of the HTC PAI-1 gene that mediate this induction. Analysis of a series of hybrid genes containing various portions of the PAI-1 5'-flanking region fused to the chloramphenicol acetyltransferase reporter gene transfected into HTC cells localized the region involved in the transcriptional regulation by glucocorticoids to between -1237 and -764. Electrophoretic mobility shift assays and DNase-I protection assays showed that a glucocorticoid response element (GRE) 15-mer located at -1212 bound the glucocorticoid receptor DNA-binding domain protein in a concentration-dependent manner. Mutations created within this GRE eliminated its ability both to confer a glucocorticoid response and to bind the glucocorticoid receptor. When placed upstream of a heterologous promoter in either orientation, this GRE conferred glucocorticoid inducibility. We, therefore, conclude that the sole cis-acting sequence required for the glucocorticoid response of the PAI-1 gene in rat HTC hepatoma cells is the GRE at -1212.
 ...
PMID:Mechanism of glucocorticoid induction of the rat plasminogen activator inhibitor-1 gene in HTC rat hepatoma cells: identification of cis-acting regulatory elements. 824 19

We determined the plasma antigen levels of urokinase-type plasminogen activator(u-PA) and plasminogen activator inhibitor 2(PAI-2) in 41 patients with hepatocellular carcinoma and 28 patients with different stages of liver cirrhosis. No significant differences of u-PA and PAI-2 levels were calculated between the two groups of tumor patients (HCC) and liver cirrhosis without tumor (non-HCC). Within both study groups, no significant differences were found in u-PA and PAI-2 levels of the different Child categories. Discriminative functions of both u-PA and PAI-2 (total error count estimates of 43.1% and 43.6%, respectively), were low compared to that (29.0%) of alpha-fetoprotein (AFP). The combinations of AFP and u-PA lowered the total error rate (21.9%) more than that of each marker alone. However, whether plasma u-PA and PAI-2 may be considered as a risk factor further investigation was needed and our findings raise the question as to whether these markers could be considered as useful screening markers for earlier detection of HCC in liver cirrhosis because discriminant functions of u-PA and PAI-2 were not significant. Sensitivities and specificities of u-PA and PAI-2 were also not high enough, resulting in the ranges of total diagnostic efficiency from 43% to 50%, and, from 49% to 63%, respectively, at different cut-off values. No direct relationship was detected between AFP and u-PA, between AFP and PAI-2, and between u-PA and PAI-2.
 ...
PMID:Diagnostic efficacy of plasma urokinase-type plasminogen activator and plasminogen activator inhibitor-2 in differentiation of hepatocellular carcinoma from cirrhosis. 857 13

We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also contained small dysplastic hepatocytes and oval-like cells, similar to those found in the tumors. Transplantation of the transgenic liver tissues harboring only dysplasia with or without vascular lesions onto nude mice was able to yield HCCs composed of small diploid cells, suggesting that initiated cells are generated during the early dysplastic phase and can progress to HCC. It is therefore likely that large dysplastic hepatocytes undergo apoptosis, which may be closely associated with the up-regulation of TGF-beta 1 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dysplasia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogenesis.
 ...
PMID:Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. 870 81

Various antibacterial compounds, antitumor compounds, enzyme inhibitors and recent signal transduction inhibitors have been discovered from microorganisms and plants. Therefore, it should be possible to find antimetastatic compounds from these sources, if a simple assay system is available. We isolated several enzyme inhibitors from nature to inhibit experimental metastasis. Leupeptin is an old protease inhibitor and inhibited blood-borne lung metastasis of hepatoma cells in rats. A leupeptin analogue inhibiting urokinase inhibited in vitro invasion of human fibrosarcoma cells. Alpha-glucosidase inhibitors such as epi-CPL and baicalein inhibited in vitro invasion and in vivo metastasis of mouse melanoma cells. A mannosidase inhibitor, mannostatin A, also inhibited in vitro invasion of mouse melanoma cells. Oncogene function inhibitors induce normal phenotypes in the oncogene-expressing cells. As expected, they inhibited tumor cell invasion in vitro.
 ...
PMID:Inhibition of experimental metastasis by enzyme inhibitors from microorganisms and plants. 886 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>