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)

Measurements of serum concentrations of des-gamma-carboxy-prothrombin (PIVKA-II) are widely used for diagnosing hepatocellular carcinoma (HCC). Recently, when we evaluated the correlation of PIVKA-II between two commercially available PIVKA-II immunoassay kits (Lumipulse f vs. Picolumi) to introduce it in our hospital, false high values of PIVKA-II were observed in Lumipulse assay. Four(4%) of 100 serum samples showed false high values, and all of them were obtained from patients less than 2 month after curative resection of HCC. Examining additional 7 patients with HCC resection, serum samples from the 5 patients had the same trend. To elucidate the non-specific reaction by Lumipulse assay which utilized alkaline phosphatase (ALP) enzymatic reaction, inhibition assays by various absorbents such as inactive ALP and IgM antibodies were performed. Excess of inactive ALP reduced the high values of PIVKA-II. Note that anti-bleeding sheets (fibrinogen combined drug), which included bovine thrombin, were directly attached on liver of all patients with HCC resection in this study. As the sheets also contaminate ALP and probably produce IgM antibodies to ALP, the IgM may cross-react with anti-PIVKA-II antibodies directly. Taken together, it was suggested that produced antibodies against ALP derived from anti-bleeding sheets led false high values of PIVKA-II in the patients with HCC resection.
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PMID:[False positive serum des-gamma-carboxy prothrombin after resection of hepatocellular carcinoma]. 1751 Dec 63

Prothrombin is a plasma protein, which after tissue injury is converted to alpha-thrombin and is mainly involved in blood clot formation. It has also been shown to have a mitogenic effect on primary endothelial cells, vascular smooth muscle cells, fibroblasts and some tumor cells, but is an inhibitor of rat hepatocyte DNA synthesis on fibronectin matrix in cell culture. We now report that prothrombin is converted to alpha-thrombin by primary cultures of normal adult rat hepatocytes and alpha-thrombin is also a potent inhibitor of hepatocytes DNA synthesis. In contrast, rat hepatoma cells cultured under similar conditions were resistant to alpha-thrombin mediated DNA synthesis inhibition. The inhibitory effect of alpha-thrombin on DNA synthesis was antagonized by hirudin and antithrombin, two specific alpha-thrombin inhibitors or by the presence of collagen-I matrix. A thrombin receptor activating peptide (TRAP6) also inhibited EGF-mediated rat hepatocyte DNA synthesis, suggesting a role of the thrombin receptors in this process. Matrix fibronectin was degraded by alpha-thrombin. However, no appreciable cell detachment was observed. These results suggest a role of alpha-thrombin as a potent growth inhibitor of normal hepatocytes, possibly through control of fibronectin or other matrix protein(s).
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PMID:alpha-Thrombin inhibits DNA synthesis in rat hepatocytes but not in hepatoma cells by receptor activation and proteolysis. 1751 31

Lack of sensitive and specific biomarkers is a major reason for the high rate of hepatocellular carcinoma (HCC) related mortality. The aim of this study was to use surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy (SELDI-TOF-MS) technology to identify potential protein patterns specific for HCC. Eighty-one patients with hepatitis B-related HCC and 80 healthy controls were randomly divided into a training set (48 HCC, 47 controls) and a testing set (33 HCC, 33 controls). Serum proteomic profiles were measured using SELDI-TOF-MS. A classification tree was established by Biomarker Pattern Software. Candidate biomarkers were separated by HPLC and identified by MALDI-MS/MS and database searching. Forty-eight HCC cases, 54 liver cirrhosis cases and 42 healthy people were clinically validated using candidate biomarkers by SELDI-Immunoassay. Two up-regulated protein peaks were automatically chosen as a classification tree in the training set. These biomarkers were identified as thrombin light chain and growth related oncogene-alpha (GRO-alpha). The sensitivity and specificity of this classification tree were 89.6%. The multivariate model using the two biomarkers and AFP resulted in a sensitivity of 91.7% and specificity of 92.7%, which was significantly better than that of alpha-fetoprotein alone. We conclude that thrombin light chain and GRO-alpha are potential biomarkers of HCC.
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PMID:Identifying serological biomarkers of hepatocellular carcinoma using surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy. 1926 39

Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR1 and PAR4 suggesting a role of these proteinase-receptor systems in HCC progression. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound of green tea on thrombin-PAR1/PAR4-mediated hepatocellular carcinoma cell invasion and p42/p44 MAPKinase activation. In this study we used the permanent liver carcinoma cell line HEP-3B and two primary cultures established from surgically resected HCCs. We found that stimulation of HCC cells with thrombin, the PAR1-selective activating peptide, TFLLRN-NH2, and the PAR4-selective activating peptide, AYPGKF-NH2, increased cell invasion across a Matrigel-coated membrane barrier and stimulated activation of p42/p44 MAPKinase phosphorylation. Both the effects on p42/p44 MAPKinases, and on cell invasiveness induced by thrombin and the PAR1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells as a previously unrecognized mode of action for EGCG in cancer cells. Moreover, the results suggest that (-)-epigal-locatechin-3-gallate might have therapeutic potential for hepatocellular carcinoma.
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PMID:Green tea polyphenol epigallocatechin-3-gallate inhibits thrombin-induced hepatocellular carcinoma cell invasion and p42/p44-MAPKinase activation. 1936 Mar 2

The expression of tissue factor (TF) in tumors reportedly exacerbates the aggressiveness of several types of cancers. The shedding of TF-containing membrane particles is believed to influence the ability of tumors to expand and metastasize, and these microparticles may also be harmful in the onset of disseminated intravascular coagulation in specific cancers. Furthermore, the intracellular signaling that is elicited after the formation of the TF / coagulation factor VIIa complex at the cell membrane modulates the activity of adhesion molecules and mitogen-activated protein (MAP) kinases. To evaluate whether TF overexpression in tumor cells modulates its shedding and neighboring stromal cells by its catalytic or intracellular activity, TF-GFP (green fluorescent protein) and a tailless form (TFDeltaC-GFP) were stably expressed in the rat Morris hepatoma and human HT1080 fibrosarcoma cell lines. Both TF proteins were efficiently produced by tumor cells and functionally active, and their clotting activity could be blocked by the active site-inhibited factor VIIa (ASIS). TF-expressing tumorigenic cells produced a soluble factor that increased the migration of arterial smooth muscle cells in vitro. This effect was abrogated by ASIS and the PAR-1 receptor antagonist ATAP-2, showing that it is dependent on the proteolytic activity of the TF ligand factor VIIa and the thrombin-activated cell membrane receptor. We propose that TF-containing microparticles that are released in the culture medium by tumor cells influence the migratory behavior of neighboring stromal cells, thus aiding the cancer cell's tumorigenic potential.
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PMID:Tumor cells expressing tissue factor influence the migration of smooth muscle cells in a catalytic activity-dependent way. 1979 20

Here, we diagnosed a Turner syndrome patient complicated with well differentiated hepatocellular carcinoma. The patient had an extremely high level of plasma fibrinogen. However, her clinical features and coagulation test abnormalities were quite different from those reported cases. We investigated the mechanisms underlying the hyperfibrinogenemia and its effects on coagulation tests. Plasma fibrinogen was analyzed by Clauss, immunoturbidimetry and Western methods. The fibrinogen genes were sequenced. Activated partial thromboplastin time, prothrombin time and thrombin time were measured. Fibrinogen expression in tumor tissues was examined immunohistochemically. Plasma cortisone, interleukin 6 and soluble tissue factor were measured by immunoassays. We found that abundant fibrinogen protein was detected in tumor cells. Plasma fibrinogen activity and antigen were 14.4 +/- 0.8 and 15.1 +/- 0.3 g/l, respectively. On SDS-PAGE, patient and control fibrinogen subunits migrated similarly. No mutations were found in the fibrinogen genes. Activated partial thromboplastin time, prothrombin time and thrombin time were significantly prolonged, but were normalized when fibrinogen was partially absorbed by an antifibrinogen antibody. Plasma interleukin 6, cortisone and soluble tissue factor levels were increased as compared with those of controls. After tumor resection, plasma fibrinogen level and other laboratory tests returned to normal. Our results showed that the hyperfibrinogenemia was caused by hepatocellular carcinoma. High levels of plasma cortisone and interleukin 6 may also contribute to the hyperfibrinogenemia. With the increase of levels of plasma fibrinogen, the values of activated partial thromboplastin time, prothrombin time and thrombin time were gradually prolonged, probably due to the effect of fibrin on thrombin (antithrombin I) and restricted fibrin polymerization by superfluous fibrinogen.
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PMID:Hyperfibrinogenemia and prolonged clotting times in a Turner syndrome patient with hepatocellular carcinoma. 2041 Aug 14

Clinical investigations and animal studies suggest haemophilia specific effects on cancer-related mortality aside from virus induced malignancies. Analysis of results in the literature proposes that coagulation factor deficiency might inhibit cancer metastasis through decreased activation of thrombin. On the other hand, substitution of coagulation factor might increase cancer rates. A review of epidemiological studies was conducted to survey the clinical data on cancer rates. Clinical investigations concerning cancer-related mortality in haemophilia always deal with virus-related malignancies caused by HIV and/or hepatitis C virus (HCV) infections. Therefore, analysis of cancer rates and standardized mortality ratios (SMR) of cancer in the literature was conducted under exclusion of HIV infection and concomitant malignancies like non-Hodgkin-lymphomas and under exclusion of HCV-related deaths caused by liver disease and hepatocellular carcinoma. The survey covers epidemiological studies which report causes of deaths of more than 8000 haemophilia patients, including more than 2700 HIV-negative patients. Results show virus independent cancer rates of 8-16% of deaths. Analysis of corresponding SMRs supports the hypothesis that cancer rates, unaffected through HIV or hepatoma, are decreased in haemophilia when compared with the general population. Prospective data collection regarding factor consumption as well as severity of haemophilia in virus negative cancer patients is needed to investigate the interaction between haemophilia and cancer.
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PMID:Does haemophilia influence cancer-related mortality in HIV-negative patients? 2072 43

The properties of human hepatoma cell lines in relation to their ability to aggregate isolated human platelets were investigated because of the possible relevance to tumour metastasis. Mahlavu, HepG2 and SK55 cells were all able to aggregate platelets irreversibly, but required the presence of small amounts of plasma, which could not be replaced by fibrinogen or other common plasma proteins. They also required the presence of Ca(2+). The plasma factor was non-dialysable and heat-labile. In the case of Mahlavu cells and SK55 cells the aggregatory activity was released from the cells as a non-dialysable material of high molecular weight. HepG2 cells were required intact and did not release materials which induced platelet aggregation. In all cases the aggregation was inhibited by hirudin. However, the requirements for plasma factors suggested that the material was not thrombin itself. The aggregatory property of all the cells was inhibited by prostacyclin and in the case of Mahlavu and HepG2 cells, to a lesser extent by nitric oxide. Addition of very small numbers of bovine aortic endothelial cells (but not human umbilical cord cells) inhibited the aggregation induced by Mahlavu and HepG2 cells, but not SK55 cells. If the endothelial cells were pre-treated with aspirin, this inhibitory property was abolished, indicating that a cyclo-oxygenase product was the principal agent.
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PMID:Interactions between Platelets and Human Hepatoma Cell Lines: The Influence of Endothelial Cells. 2104 59

We developed a novel on-chip assay using protein arrays for quantitative and rapid analysis of blood coagulation factor XIII (FXIII) activity in human plasma. FXIII is activated by concerted action of thrombin and Ca(2+) and plays essential roles in hemostasis, angiogenesis, and wound healing. We fabricated protein arrays by immobilizing fibrinogen onto the 3-aminopropyltrimethoxysilane layer of well-type arrays and determined FXIII activity by analyzing biotinylated fibrinogen with Cy3-conjugated streptavidin. We determined optimal concentrations of Ca(2+), thrombin, and 5-(biotinamido)pentylamine (BAPA) for the on-chip activity assay, and the detection limit was 0.01 Lowey U/mL (9.9 pM). Using the on-chip activity assay, hepatocellular carcinoma patients (n = 24), but not hepatitis (n = 24) or liver cirrhosis patients (n = 41), had significantly lower FXIII activities (p < 0.001) than normal individuals (n = 41), indicating that FXIII activity is a possible diagnostic marker for hepatocellular carcinoma. In addition, we have successfully used this activity assay to reveal individual variations (37-57%, n = 65) in the inhibition rate of FXIII activity by isoniazid, the first-line antituberculosis agent. Thus, our optimized on-chip FXIII activity assay provides a quantitative and high-throughput approach to investigating the role(s) of FXIII in human diseases. Moreover, it has a strong potential to be applied toward FXIII-related personalized medicines.
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PMID:Rapid determination of blood coagulation factor XIII activity using protein arrays for serodiagnosis of human plasma. 2132 42

In order to investigate the relationship between hemostatic abnormalities and portal vein thrombosis (PVT) in hepatocellular carcinoma (HCC), platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, d-dimer, fibrinogen degradation products (FDPs), protein C, protein S, antithrombin, plasminogen, antiplasmin, coagulation factors (CFs) V, VII, VIII, IX, XI, and XIII, von Willebrand factor (vWF), prothrombin fragment 1 + 2 (PF 1 + 2), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor 1 (PAI-1) were studied in patients with HCC, cholangiocarcinoma, and metastatic liver tumors and in cirrhosis patients with or without PVT. Platelet, antithrombin, protein C, plasminogen, and CFs V, VII, IX, XI, and XIII levels of HCC group were found lower and PT, aPTT, thrombin time, vWF, FDPs, PF 1 + 2, tPA, and PAI-1 levels were higher than the control group. Our findings suggested that the abnormalities of coagulation and fibrinolysis systems have some role in provoking thrombosis of portal veins in HCC, in addition to the invasion of portal veins by hepatoma cells.
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PMID:Hemostatic abnormalities in cirrhosis and tumor-related portal vein thrombosis. 2216 87


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