UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The induction of proteolytic enzymes is an important mechanism in the migration of monocytes into tissues and body fluids. The monocytic cell line THP-1 was used as a model system to study the production of a particular gelatinase. Upon stimulation with phorbol myristate acetate (PMA) the cells differentiated to the adherent phenotype and produced significant amounts of a 96-kD gelatinase in a dose-dependent way. The secretion rate was maximal between 12 and 24 h after induction. Study of gelatinase mRNA steady state levels showed that the synthesis of THP-1 gelatinase is regulated by PMA at transcriptional or posttranscriptional levels. Stimulation of signal transduction pathways with other substances, including calcium ionophore A 23187, dibutyryl cyclic AMP, and dexamethasone, were ineffective in inducing gelatinase mRNA or enzyme activity. However, THP-1 cells were responsive to the cytokine interleukin (IL)-1 beta, to bacterial lipopolysaccharide (LPS), and the lectin concanavalin A (Con A), the kinetics of gelatinase induction being similar to those of induction by PMA. The THP-1 cells did not synthesize and/or secrete detectable levels of IL-6 after stimulation with PMA, Con A, LPS, or IL-1 beta. The 96-kD monocytic THP-1 gelatinase was shown to be a neutral metalloproteinase that cross-reacted with hepatoma-derived and neutrophil gelatinases in immunoprecipitation experiments. The active enzyme produced by THP-1 cells consistently showed, however, a molecular mass different from that of normal granulocyte-, monocyte-, and tumor cell-derived gelatinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cytokine-protease connection: identification of a 96-kD THP-1 gelatinase and regulation by interleukin-1 and cytokine inducers. 165 55

Metalloproteinase inhibitors were surveyed with the culture media of 19 kinds of human tumor cell lines, using transin (rat stromelysin) as the target enzyme. This survey showed that most of the cell lines more or less secreted inhibitor activity, and that a human hepatoma cell line, HLE, secreted an extremely high inhibitor activity into the culture medium. Two kinds of metalloproteinase inhibitors were purified from the serum-free conditioned medium of HLE cells. The major inhibitor, which showed a single protein band with a molecular weight (Mr) of 21,000 (21k) (nonreduced) or 24k (reduced) on SDS-polyacrylamide gel electrophoresis, was identified as TIMP-2 (tissue inhibitor of metalloproteinases-2) by the analysis of its N-terminal amino acid sequence. The other was immunologically identified as TIMP. Purified TIMP-2 inhibited the activities of transin, matrin (pump-1), Mr 72k gelatinase, and interstitial collagenase with 1:1 stoichiometry. When the latent precursor form (Mr 57k) of transin was incubated with p-aminophenylmercuric acetate as an activating reagent, TIMP-2 inhibited the conversion of the intermediate form (Mr 45k) into the mature enzyme (Mr 42k). This indicated that TIMP-2 regulates not only the activity of the mature enzyme but also the autolytic processing of the proenzyme. TIMP-2 also inhibited in vitro tumor invasion through reconstituted basement membrane (matrigel) in chemotaxis chambers, showing that the metalloproteinase inhibitors as well as the extracellular matrix metalloproteinases are involved in tumor invasion through basement membrane and other extracellular matrices.
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PMID:Efficient purification of TIMP-2 from culture medium conditioned by human hepatoma cell line, and its inhibitory effects on metalloproteinases and in vitro tumor invasion. 166 1

Several human cell lines were studied for the production of gelatinases. Diploid fibroblasts, the melanoma cell line Bowes, the MG-63 osteosarcoma cell line and the human hepatoma cell line Malavu all constitutively produced a 67 kDa gelatinase. Gelatinolytic enzymes were quantified by a sensitive zymographic substrate conversion assay. Upon induction with phorbol 12-myristate 13-acetate (PMA), the human hepatoma cell line secreted considerable amounts of an 85 kDa gelatinase activity. The induction process was time- and dose-dependent. It represented a true increase in production per individual cell and was associated by a marked change of the cell morphology. The effect of various proteinase inhibitors and the maximal activity of the enzyme near neutral pH demonstrate that it is a neutral metalloproteinase. Characterization studies showed the 85 kDa gelatinase to be transformed to lower molecular weight, active forms by treatment with p-aminophenylmercuric acetate (APMA) or trypsin.
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PMID:Human hepatoma cells produce an 85 kDa gelatinase regulated by phorbol 12-myristate 13-acetate. 216 96

Studies of tissue inhibitors of metalloproteinases (TIMPs) suggest that one of their main functions is to inhibit metalloproteinase (MMP) activity and thus prevent tumor invasion by preserving extracellular matrix (ECM) integrity. In the present study we examined the distribution of transcripts for TIMP-1, MMP-2 and MMP-9 in monkey hepatocellular carcinoma tissues. In situ hybridization demonstrated elevated levels of TIMP-1 transcripts in fibrous tissue septa, tumor inflammatory infiltrate, tumor blood vessels and in expanded portal areas. However, elevated transcripts for MMP-2 and MMP-9 were found only in tumor inflammatory infiltrate. In lung metastasis high levels of TIMP-1 transcripts were found in the stromal cells surrounding necrotic tumor nodules, in tumor blood vessels, and in mesothelial cells. MMP-9 transcripts were elevated at the periphery of the necrotic tumor nodules. These findings suggest that TIMP-1 and type IV collagenases/gelatinases can be independently regulated in vivo and that TIMP-1 may have functions in ECM remodeling which are unrelated to inhibition of MMP activity.
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PMID:Localization of messenger RNA for tissue inhibitor of metalloproteinases-1 and type IV collagenases/gelatinases in monkey hepatocellular carcinomas. 764 22

We examined four commercially available human cell lines for endothelin-converting-enzyme-(ECE) like activity and compared the results with primary porcine aortic endothelial cell enzymes. The cells that were investigated were 293 (transformed primary human embryonal kidney), Hep G2 (human hepatocellular carcinoma), HUVECs (human umbilical vein endothelial cells), and U937 (human histiocytic lymphoma). The relative ECE-like activities were determined in cytosolic and particulate extracts of each cell type. Enzyme activity against pro-ET-1 was measured at pH 4 and 7, using a C-terminal Trp-specific antibody to ET-1 radioimmunoassay and by high-performance liquid chromatography analysis of the enzyme hydrolysis products of pro-ET-1. Inhibition by EDTA at pH 7 or pepstatin at pH 4 was used to classify the pro-ET-1 processing enzymes from the human cell lines as either metallo- or aspartylproteinases. The particulate extract of the primary porcine aortic endothelial cells contained both aspartyl and metallo ECE-like enzymes. No ECE-like activity was present in either the cytosolic or particulate extracts of the U937 nor 293 cells. Neither the particulate extract of the Hep G2 cells nor the cytosolic extract of the HUVECs had any ECE-like activity. The cytosolic extract of the Hep G2 cells and the particulate extract of the HUVECs had an ECE-like activity at pH 7 that was inhibited by 10 mM EDTA, qualifying these enzymes as members of the metalloproteinase family.
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PMID:A comparison of endothelin-converting enzyme activity from primary porcine aortic endothelial cells with activities in cultured human cell lines. 812 Nov 80

To examine the clinical significance of serum collagenase activity in chronic liver disease, serum collagenase activity was determined in 50 patients with chronic liver disease and in 24 healthy controls. Collagenase activity was measured after reactivation by denaturing and dissociating the inhibitors with potassium thiocyanate and aminophenylmercuric acetate. In patients with chronic persistent hepatitis, serum collagenase activity was 37% lower than controls, 50% lower in those with chronic active hepatitis, 66% lower in those with cirrhosis and 68% lower in those with hepatocellular carcinoma. Serum collagenase activity was significantly and inversely correlated with serum levels of the aminoterminal propeptide of type III procollagen and type IV collagen 7S domain, indicating that serum collagenase activity decreased as liver active fibrogenesis and/or fibrosis occurred. In contrast, serum levels of the metalloproteinase inhibitor was 30% higher than controls in patients with chronic active hepatitis, 50% higher in those with cirrhosis and 80% higher in those with hepatocellular carcinoma and was inversely correlated with serum collagenase activity. These results suggest that in this assay condition serum collagenase activity is influenced by the metallo-proteinase tissue inhibitor and thus does not reflect the amount of collagenase in the fibrotic liver.
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PMID:Serum collagenase activity in patients with chronic liver disease. 822 26

The prognosis for hepatocellular carcinoma (HCC) depends mainly on the clinicopathological characteristic regarding invasion and metastasis. In addition, another distinguishing feature of HCC is the high incidence of concomitant liver cirrhosis, in which the extracellular matrix proliferates markedly. Therefore, the present study was designed to investigate the molecules responsible for the invasion potential of HCC by focusing on matrix metalloproteinase (MMP) in particular, MMP-2 and MMP-9 and the corresponding tissue inhibitor of metalloproteinase (TIMP-2 and TIMP-1), because these enzymes participate in the degradation of the extracellular matrix including the basement membrane. Tumorous and adjacent nontumorous liver samples were obtained from 23 HCC patients who underwent a partial hepatectomy. In 16 of the 23 HCC samples, transcripts for MMP-9 were detected in the tumorous tissues, and 15 of 16 of these samples showed stronger expression in the tumorous tissues than in the nontumorous tissues. On the other hand, MMP-2 messenger RNA (mRNA) was detected in 18 of the 23 cases. Eight of these 18 cases showed more intense expression in the tumorous tissues than in the nontumorous tissues, whereas the expression levels were lower in the tumorous tissues than in the nontumorous tissues in 7 of 18 samples. With respect to the correlation between the clinicopathological features and mRNAs expression, it was found that the expression of MMP-9 mRNA in HCC with capsular infiltration was significantly higher than in HCC without capsular infiltration. HCC with capsular infiltration also tended to have a higher ratio of MMP-9 mRNA expression to TIMP-1 mRNA expression. In addition, the expression of MMP-2 mRNA in nontumorous cirrhotic tissues was significantly higher than in nontumorous tissues from patients with chronic hepatitis. Immunohistochemical examinations revealed that MMP-9 immunoreactivity was the most intense in the HCC cells, particularly in those cells in the marginal areas of the tumorous tissues. In conclusion, the present study shows that MMP-9 is closely participated in capsular infiltration in HCC.
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PMID:Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. 869 Mar 99

Certain membrane-anchored proteins, including several cytokines and cytokine receptors, can be released into cell supernatants through the action of endogenous membrane-bound metalloproteinases. The shed molecules are then able to fulfill various biological functions; for example, soluble interleukin-6 receptor (sIL-6R) can bind to bystander cells, rendering these cells sensitive to the action of IL-6. Using IL-6R as a model substrate, we report that the metalloproteinase from Serratia marcescens mimics the action of the endogenous shedding proteinase. Treatment of human monocytes with the bacterial protease led to a rapid release of sIL-6R into the supernatant. This effect was inhibitable with TAPI [N-(D,L-[2-(hydroxyaminocarbonyl)methyl]-4-methylpentanoyl) L-3-(2' naphthyl)-alanyl-L-alanine, 2-aminoethyl amide], a specific inhibitor of the membrane-bound intrinsic metalloproteinase, but not with other conventional proteinase inhibitors. sIL-6R-liberating activity was also detected in culture supernatants of Staphylococcus aureus, Pseudomonas aeruginosa, and Listeria monocytogenes, organisms that are known to produce metalloproteinases. sIL-6R released through the action of S. marcescens metalloproteinase retained biological activity and rendered IL-6-unresponsive human hepatoma cells sensitive to stimulation with IL-6. This was shown by Northern (RNA) blot detection of haptoglobin mRNA and by quantitative measurements of de novo-synthesized haptoglobin in cell supernatants. Analysis of immunoprecipitated, radiolabeled sIL-6R revealed that the bacterial protease cleaved IL-6R at a site distinct from that utilized by the endogenous protease. These studies show that membrane-anchored proteins can be released in active form through cleavage at multiple sites, and they uncover a novel mechanism via which microbial proteases possibly provoke long-range biological effects in the host organism.
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PMID:Novel pathogenic mechanism of microbial metalloproteinases: liberation of membrane-anchored molecules in biologically active form exemplified by studies with the human interleukin-6 receptor. 875 12

The effects of dibutyryl cyclic AMP (DBcAMP) on tissue inhibitor metalloproteinase (TIMP) expression were studied in the human hepatoma cell line PLC/PRF/5 with relation to the invasive activity of the cells. Messenger RNA expression levels of metalloproteinases (MMP)-2 and 9, and TIMP-1, 2 and 3 in the cells were determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). MMP-9 and TIMP-2 mRNA expression were not detectable in the cells with or without DBcAMP treatment. Relative MMP-2 and TIMP-1 mRNA expression levels in the cells were not affected by DBcAMP, whereas TIMP-3 mRNA expression was enhanced by DBcAMP. This stimulatory effect of DBcAMP on TIMP-3 expression was confirmed at the mRNA and intracellular protein levels by Northern and Western blotting, respectively. Invasive activity of PLC/PRF/5 cells was determined using the in vitro Matrigel (extracellular matrix extract) invasion model. DBcAMP inhibited the invasive activity of the cells, and this effect was eliminated by addition of an antisense oligonucleotides corresponding to TIMP-3 mRNA. These results suggested that TIMP-3 expression is enhanced by DBcAMP and may play a role in inhibition of the invasive activity of hepatoma cells.
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PMID:Dibutyryl cyclic AMP-induced enhancement of tissue inhibitor of metalloproteinases-3 expression and its possible relation to the invasive activity of the human hepatoma cell line PLC/PRF/5. 1069 30

Thioredoxin (Trx) inhibited tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 activity with an approximate IC50 of 0.3 microM, matrix metalloproteinase (MMP)-2 activity with an approximate IC50 of 2 microM but did not inhibit MMP-9 activity. This differential capacity of Trx to inhibit TIMP and MMP activity resulted in the promotion of MMP-2 and MMP-9 activity in the presence of molar TIMP excess. Inhibition of TIMP and MMP-2 activity by Trx was dependent upon thioredoxin reductase (TrxR), was abolished by Trx catalytic site mutation and did not result from TIMP or MMP-2 degradation. HepG2 hepatocellular carcinoma cells induced to secrete Trx inhibited TIMP activity in the presence of TrxR. SK-N-SH neuroblastoma cells secreted TrxR, which inhibited TIMP and MMP-2 activity in the presence of Trx. Trx stimulated SK-N-SH invasive capacity in vitro in the absence of exogenous TrxR. This study therefore identifies a novel extracellular role for the thioredoxin/thioredoxin reductase redox system in the differential inhibition of TIMP and MMP activity and provides a novel mechanism for altering the TIMP/MMP balance that is of potential relevance to tumor invasion.
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PMID:Thioredoxin alters the matrix metalloproteinase/tissue inhibitors of metalloproteinase balance and stimulates human SK-N-SH neuroblastoma cell invasion. 1116 76

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