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)

Signal transduction in response to interleukin-6 (IL-6) results from homodimerization of gp130. This dimerization occurs after binding of IL-6 to its surface receptor (IL-6R) and can also be triggered by the complex of soluble IL-6R and IL-6. We fused IL-6 to the constant region of a human IgG1 heavy chain (Fc). IL-6Fc was expressed in COS-7 cells and purified via Protein A Sepharose. Using three different assays we found that the biological activity of this dimeric IL-6 protein is comparable with monomeric IL-6. Recently, we described the designer cytokine Hyper-IL-6 (H-IL-6) in which soluble IL-6R and IL-6 are connected via a flexible peptide linker. This molecule turned out to be 100-1000 times more effective than unlinked IL-6 and soluble IL-6R. Hyper-IL-6 acts on cells only expressing gp130 and is a potent stimulator of in vitro expansion of early hematopoietic precursors. Here we show that a Fc fusion protein of H-IL-6 (H-IL-6Fc) has the same biological activity on BAF/gp130 cells as H-IL-6. Furthermore, both H-IL-6 forms have a similar ability to induce the synthesis of acute phase proteins in human hepatoma cells HepG2 and in mice in vivo. The introduction of a thrombin cleavage site between H-IL-6 and the Fc portion of H-IL-6Fc made it possible to specifically recover biologically active monomeric H-IL-6 by limited proteolysis of the fusion protein. A more general use of cleavable immunoadhesins expressed in mammalian cells is discussed.
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PMID:Immunoadhesins of interleukin-6 and the IL-6/soluble IL-6R fusion protein hyper-IL-6. 1008 96

A new case of anti-factor V inhibitor is described in a 46-year-old man, who received a liver transplantation for hepatocellular carcinoma, without exposure to bovine thrombin or fibrin glue during the operative course. The inhibition occurred on the 14th postoperative day, while the patient was being treated with oxacillin, azathioprine, and a new immunosuppressive drug, FK506. The inhibition was of short duration (3 days), and no bleeding complication occurred despite a very low plasmatic level of factor V activity and antigen (<5%). Plasma samples drawn after cessation of FK506 disclosed a dose-dependent inhibitory activity when alcoholic solutions of FK506 were exogeneously added; this suggests a possible role of the FK506 drug in the occurrence of this anti-factor V inhibitor.
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PMID:Inhibitor against coagulation factor V after liver transplantation. 1053 50

We report a 71-year-old man who exhibited hepatocellular carcinoma and the inhibitor for coagulation factor V (FV). The inhibitor was found when his coagulation screening tests revealed an abnormally prolonged prothrombin time (71.1 sec) and activated partial thromboplastin time (more than 120 sec) but normal values of fibrinogen (241 mg/dl), the thrombo test (84%) and hepaplastin test (71%). In addition, FV-coagulation activity of the patient's plasma showed less than 1% of the pooled normal plasma and inhibitory activity for FV of his plasma was 32 Bethesda units. This inhibitory activity was neutralized by the addition of anti-human immunoglobulin-gamma-chain serum. The patient was treated with a fibrin sealant including human thrombin when he underwent an partial hepatectomy (32 months before onset) and received 2 doses of thrombin orally (5 months and 2 weeks before onset) to stop bleeding from phlebeurysm. Several studies have reported that the inhibitor for FV was produced after treatment with bovine thrombin containing FV as a contaminant. These findings suggest that our patient may produce an immunoglobulin specific for FV after similar stimulation of human thrombin containing FV.
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PMID:[A case positive for the inhibitor for coagulation factor V]. 1059 Jun 73

Recurrence of hepatocellular carcinoma (HCC) is frequent, even after apparently curative resection. Preoperative transcatheter arterial chemoembolization (TAE) does not improve disease-free survival after hepatic resection. We previously reported the potential usefulness of transarterial immunoembolization (TIE), a newly developed arterial embolization technique using OK-432 and fibrinogen, as preoperative treatment. In this study, we further investigated the effect of TIE by histologic examination of the resected specimens and compared it with conventional TAE in a prospective nonrandomized manner. Thirty-nine patients underwent TIE (n = 17) or TAE (n = 22) before curative hepatectomy for HCC. Transarterial immunoembolization was performed according to the standard protocol using OK-432, fibrinogen, and thrombin. Histologic changes in cancerous and noncancerous liver tissues were examined at different stages after TIE. Histologic grading of cancer cell injury according to the modified Shimosato criteria (Grades 0-IV, in increasing order of severity of cell injury) and postoperative disease-free survival were compared between the two groups. Based on the results of histopathology, TAE was more effective than TIE against the main tumor. In contrast, TIE was significantly more effective than TAE against extracapsular invasion and intrahepatic metastasis. Disease-free survival after hepatectomy tended to be better in patients pretreated with TIE than TAE. Postoperative tumor recurrences in the TIE group (n = 4) occurred in the nontreatment regions, whereas tumor recurrences in TAE group developed mostly (8 of 11 patients) in treated liver regions. Based on results of histologic examination, TIE seems to be more effective than conventional TAE against extracapsular invasion and intrahepatic metastasis. Data for disease-free survival and recurrence site suggest TIE may be a useful preoperative treatment.
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PMID:Appraisal of transarterial immunoembolization for hepatocellular carcinoma: a clinicopathologic study. 1115 73

Platelet-derived growth factor (PDGF) affects cell proliferation and differentiation during mammalian embryogenesis. In a number of avian species, PDGF-alpha receptors and PDGF-A chain (PDGF-A) are present during chicken limb and lens development. However, little is understood about the chicken PDGF-A gene. The present study identified short form type 1 (S1), long form (L) and short form type 2 (S2) cDNA clones encoding chicken PDGF-A chain (PDGF-A). These clones were isolated from a chicken hepatoma cell line (LMH) mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and cDNA library cloning. Genomic sequencing and Southern blotting revealed that these forms were generated by alternative splicing. The mRNAs of S1 and L contained two transcription start sites on one exon. At the amino acid level, the mature protein encoded by the L clone showed 90 and 85% homology with the processed coding regions of the long form of human and Xenopus PDGF-A, respectively. The putative mature peptides of all forms of chicken PDGF-A encompassed the eight cysteine residues conserved in all known forms of PDGF. We examined the expression of the three forms in chicken tissues and cells using RT-PCR. Expression of these forms varied among tissues and cells. Levels of PDGF mRNAs were very low in chicken thrombocytes, which are analogous to mammalian platelets. However, the level of PDGF-A chain mRNA expression in chicken thrombocytes peaked 4 h after exposure to type 1 collagen or thrombin, and then decreased gradually with continued incubation. These results suggest that chicken PDGF in thrombocytes plays an important role in the vascular system and in healing damaged tissue.
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PMID:Characterization and expression of three forms of cDNA encoding chicken platelet-derived growth factor-A chain. 1147 May 24

Thrombin-activable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase B-like zymogen that upon activation by thrombin, thrombin-thrombomodulin, or plasmin attenuates fibrin clot lysis by inhibiting positive feedback in the fibrinolytic cascade. The concentration of TAFI in plasma varies in the human population and thus may constitute a risk factor for thrombotic disorders. In addition, TAFI has been reported to be a positive acute phase reactant in mice. We have initiated molecular analysis of the human TAFI promoter to understand the mechanisms underlying regulation of TAFI gene expression. We identified a putative C/EBP-binding site between -53 and -40 of the promoter. Mutations in this site that abolish C/EBP binding decrease TAFI promoter activity in human hepatoma (HepG2) cells by approximately 80%. Gel mobility shift analyses indicated that C/EBP-beta present in HepG2 nuclear extracts and C/EBP-alpha and -beta present in adult rat liver nuclear extracts bind to the C/EBP site. C/EBP-alpha, -beta, and -delta isoforms are all capable of binding to the C/EBP site and activating the TAFI promoter. The identification of a functional C/EBP-binding site in the human TAFI promoter may have important implications for the regulation of expression of this gene during development and in response to inflammatory stimuli.
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PMID:A role for CCAAT/enhancer-binding protein in hepatic expression of thrombin-activable fibrinolysis inhibitor. 1200 Jul 65

Thyroid hormone (T(3)) regulates growth, development, and differentiation. These activities are mediated by the nuclear thyroid hormone receptors (TRs), which belong to the steroid/TR superfamily of ligand-dependent transcription factors. The effect of T(3) treatment on target gene regulation was investigated in a TRalpha-overexpressing hepatoma cell line (HepG2-TRalpha), by performing cDNA microarrays. We demonstrate that 148 of the 7597 genes represented were up-regulated by T(3), including fibrinogen and several other components of the coagulation factor system. To confirm the microarray results, fibrinogen and a small number of the blood clotting components were further investigated using quantitative RT-PCR. The T(3)-induction ratios observed with quantitative RT-PCR for factors such as thrombin (8-fold), coagulation factor X (4.9-fold), and hepatoglobin (30-fold) were similar to those observed by the cDNA microarray analysis. Further investigation, using HepG2-TRalpha (cell lines, revealed a 2- to 3-fold induction of fibrinogen transcription after 24 h of T(3) treatment. In addition, T(3) treatment increased the level of fibrinogen protein expression 2.5- to 6-fold at 48 h. The protein synthesis inhibitor, cycloheximide, did not inhibit the induction of fibrinogen by T(3), indicating that this regulation was direct. Furthermore, transcription run-on experiments indicate that the induction of fibrinogen by T(3) is regulated largely at the level of transcription. Similar observations were made on the regulation of fibrinogen by T(3) using rats that received surgical thyroidectomy (TX) as an in vivo model. These results suggest that T(3) plays an important role in the process of blood coagulation and inflammation and may contribute to the understanding of the association between thyroid diseases and the misregulation of the inflammatory and clotting profile evident in the circulatory system of these patients.
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PMID:Thyroid hormone receptor-dependent transcriptional regulation of fibrinogen and coagulation proteins. 1497 60

The liver plays a central role in haemostasis, being the site of synthesis of most of the clotting factors, coagulation inhibitors and fibrinolytic parameters, in addition to its clearance of activated clotting and fibrinolytic factors. Nonetheless, no haemostatic test(s) is included among the routine liver function tests and this study aims to probe this possibility. The liver disease group (n=258) included acute hepatitis (n=25), chronic viral hepatitis (n=128), hepatitis B (HB) carriers (n=25), liver cirrhosis (n=67), and hepatocellular carcinoma (HCC) (n=13). The prothrombin time was significantly prolonged in acute hepatitis, liver cirrhosis and HCC. However, the reptilase time was prolonged in all the groups except in HB carriers, while the thrombin time was prolonged only in the HCC group. Antithrombin III and protein C levels exhibited significant reduction in acute hepatitis, liver cirrhosis and HCC. On the other hand, protein S levels (total and free) were reduced significantly in all the patients groups, including HB carriers when compared with healthy controls. Derangement of haemostatic tests is a common feature in liver disease, being most significant in acute hepatitis, liver cirrhosis and hepatocellular carcinoma. The most sensitive markers of hepatocyte malfunction are protein S (total and free) and the reptilase time as they were abnormal, in the mildest liver affections, when other biochemical tests as well as other haemostatic tests were normal. Further studies are needed to see whether these two tests qualify for inclusion among the routine liver function tests.
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PMID:Haemostatic abnormalities in liver disease: could some haemostatic tests be useful as liver function tests? 1597 Jul 16

Thrombin, acting via protease-activated receptors (PARs), and tissue factor (TF) are involved in inflammation, tissue repair and tumorigenesis. Hepatocellular carcinomas (HCCs) usually complicate chronic liver diseases characterised by inflammation and fibrosis. The aim of this study was to describe the expression of PARs and TF in normal liver, cirrhosis and HCCs. We performed an immunohistochemical detection of PAR-1, PAR-3, PAR-4 and human TF in human tissue samples from 19 subnormal livers, 33 cirrhosis and 30 HCCs. PAR-1 was found on endothelial cells of sinusoids and larger vessels. In cirrhosis, spindle-shaped cells within septa and T lymphocytes were PAR-1 positive. A few PAR-1-positive tumour cells were found in 10% of HCCs. PAR-4 expression was restricted to macrophages, B lymphocytes and nerves. PAR-3 expression was rare. Unexpectedly, TF was expressed in 95% of normal livers and in 94% of cirrhosis but only in 50% of HCCs (p<0.001). Staining was mostly hepatocellular. No association existed between TF labelling and clinicopathological characteristics of HCCs. In conclusion, the pattern of expression of PARs is compatible with its role in chronic liver disease by promoting inflammation via immune cells and neurogenic stimulation. However, our data do not support a role for PARs or TF in HCC progression.
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PMID:Expression of protease-activated receptors and tissue factor in human liver. 1619 94

Proteinase-activated receptor-1 (PAR(1)), a thrombin receptor and the prototype of a newly discovered G-protein-coupled receptor subfamily, plays an important role in tumor development and progression. In this study, we documented the expression of the thrombin receptors PAR(1), PAR(3), and PAR(4) in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR(1)-selective activating peptide, TFLLRN-NH(2), increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR(1) antagonist SCH 79797, confirming that the PAR(1) thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR(4)-selective agonist, AYPGKF-NH(2), also stimulated HCC cell migration whilst the PAR(4) antagonist, trans-cinnamoyl-YPGKF-NH(2), attenuated the effect of thrombin on HCC cell migration. PAR(1)- and PAR(4)-triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the G(i)/G(o) family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP-dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR(1)/PAR(4) signaling network that contributes to thrombin-mediated tumor cell migration. We suggest that a combined inhibition of coagulation cascade serine proteinases, the two PARs and their complex signaling pathways may provide a new strategy for treating hepatocellular carcinoma.
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PMID:Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. 1732 77


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