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)

Protein C inhibitor (PCI) is a plasma serine protease inhibitor of activated protein C, which is the main protease of the anticoagulant protein C pathway. Human PCI is synthesized in the liver, kidney, and several reproductive organs (testis, seminal vesicle, and prostate). In the present study, we characterized cis-elements of the human PCI gene required for expression in the hepatoma-derived cell line, HepG2 cells, and also evaluated rat PCI mRNA expression, particularly on the effect of androgen in rat reproductive tissues. On the PCI gene expression in HepG2 cells, transient expression assays using several deletion mutants and site-directed mutants of the human PCI gene and gel mobility shift assays using several synthetic oligonucleotides showed that the Spl-binding site (residues -302 to -294) and the upstream AP2-binding site (residues -350 to -343) play roles as the promoter and the enhancer, respectively. Both the A-activator-binding site (residues -422 to -414) and the interferon-gamma response element (residues -164 to -157) serve as the silencer. In the study on PCI mRNA expression in the reproductive organs, we first cloned rat PCI cDNA and then evaluated the effect of androgen on the PCI mRNA expression. The isolated rat PCI cDNA contained a 1,218-bp coding region of a 406-amino acid precursor protein. The deduced amino acid sequence of rat PCI showed an 85.7% and 62.2% homology with that of mouse and human PCIs, respectively. Northern blot analysis showed that rat PCI mRNA was strongly expressed in the seminal vesicles, moderately in the testes, but not in the liver. PCI mRNA expression in seminal vesicles and testes increased during the process of development. The PCI mRNA expression in seminal vesicles was significantly decreased after castration or after 17beta-estradiol treatment. Treatment with testosterone in the castrated rats significantly enhanced its mRNA expression. These findings suggest that the PCI gene expression in rat seminal vesicles is under androgen control.
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PMID:cis-elements required for expression of human protein C inhibitor gene in HepG2 cells and its androgen-dependent expression in rat reproductive organs. 1080 86

Asparaginase (ASNase) is a widely used and successful agent against childhood acute lymphoblastic leukemia (ALL). Asparaginase cleaves asparagine (Asn) to give aspartic acid and ammonia, thereby depleting free Asn in the blood. However, treatment with ASNase has been implicated in significant reduction of plasma levels of the coagulation serine protease inhibitor (serpin) antithrombin III (AT3), predisposing patients to thromboembolic complications. Our investigation was designed to delineate the biochemical mechanism of AT3 depletion that can occur in the plasma of ALL patients undergoing ASNase therapy. SDS-PAGE showed no cleavage of purified AT3 following treatment with ASNase. Furthermore, purified AT3 treated with ASNase demonstrated no decrease in inhibitory activity. Human plasma and whole blood treated with approximate therapeutic concentrations of ASNase showed no loss of AT3 activity as detected by a plasma-based factor Xa inhibition assay. Treatment of a confluent monolayer of HepG2 (hepatocarcinoma) cells with ASNase showed no gross loss in AT3 message levels detected by rtPCR. However, a decrease of cell viability was observed in cultures treated with ASNase. Interestingly, medium from HepG2 cells treated with ASNase showed a marked decrease in secretion of AT3 and another serpin, heparin cofactor II. Collectively, these data show that ASNase has no direct effect on AT3 in blood or plasma, but that ASNase may affect plasma levels of AT3 by interfering with translation and/or secretion of the protein in liver cells.
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PMID:Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. 1086 29

The human gene encoding alpha1-antitrypsin (alpha1AT, gene symbol PI) resides in a cluster of serine protease inhibitor (serpin) genes on chromosome 14q32.1. alpha1AT is highly expressed in the liver and in cultured hepatoma cells. We recently reported the chromatin structure of a >100 kb region around the gene, as defined by DNase I-hypersensitive sites (DHSs) and matrix-attachment regions, in expressing and non-expressing cells. Transfer of human chromosome 14 by microcell fusion from non-expressing fibroblasts to rat hepatoma cells resulted in activation of alpha1AT transcription and chromatin reorganization of the entire region. In the present study, we stably introduced cosmids containing alpha1AT with various amounts of flanking sequence and a linked neo selectable marker into rat hepatoma cells. All single-copy transfectants with >14 kb of 5' flanking sequence expressed wild-type levels of alpha1AT mRNA in a position-independent manner. In contrast, expression of transgenes containing only approximately 1.5-4 kb of flanking sequence was highly variable. Long-term culture of transfectant clones in the absence of selection resulted in gradual loss of neo expression, but expression of the linked alpha1AT gene remained constant. DHS mapping of cosmid transgenes integrated at ectopic sites revealed a hepatoma-specific chromatin structure in each transfectant clone. The implications of these findings are discussed.
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PMID:Stable expression and cell-specific chromatin structure of human alpha1-antitrypsin cosmid transgenes in rat hepatoma cells. 1098 83

The RECK (reversion-inducing-cysteine-rich protein with Kazal motifs) gene was initially isolated as a transformation suppressor gene. It encodes a membrane-anchored glycoprotein with multiple serine protease inhibitor-like domains. The RECK gene is expressed widely in normal organs but is undetectable in many tumor-derived cell lines. When artificially expressed in such cell lines, RECK suppresses their invasive and metastatic activities. Clinical implications of these findings, however, remained undefined because of the lack of studies using fresh human tumor samples. In the present study, we have addressed this issue by analyzing the levels of RECK gene expression in hepatocellular carcinoma (HCC). RECK mRNA was detectable by RNA blot hybridization in all the tumorous and contiguous nontumorous tissues obtained from 64 patients with HCC. In 26 cases, the RECK expression in tumorous tissues was higher than that in nontumorous tissues. The expression of RECK protein in these tissues could also be demonstrated by immunohistochemistry. Patients with high RECK mRNA expression in tumorous tissues tended to show better survival (P =.02), and such tumors had a tendency to be less invasive. Univariate and multivariate analysis revealed that the RECK mRNA expression is a novel and independent variable affecting overall survival (P =.01). These findings support the hypothesis that RECK has negative effects on the invasiveness of HCC cells and suggest the feasibility of RECK mRNA as a promising prognostic molecular marker for HCC.
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PMID:RECK gene expression in hepatocellular carcinoma: correlation with invasion-related clinicopathological factors and its clinical significance. Reverse-inducing--cysteine-rich protein with Kazal motifs. 1112 35

Persistent infection with hepatitis C virus (HCV) may lead to hepatocellular carcinoma (HCC). It has been suggested that HCV-encoded proteins are directly involved in the tumorigenic process. The HCV nonstructural protein NS3 has been identified as a virus-encoded serine protease. To study whether HCV NS3 has oncogenic activity, nontumorigenic rat fibroblast (RF) cells were stably transfected with an expression vector containing cDNA for the NS3 serine protease (nucleotides 3356-4080). The NS3 serine protease activity was determined in the transfected cells. The transfected cells grew rapidly and proliferated serum independently, lost contact inhibition, grew anchorage independently in soft agar and induced significant tumour formation in nude mice. Cells transfected with an expression vector containing a mutated NS3 serine protease (serine 139 to alanine at the catalytic site) showed no transforming abilities; their growth was dependent on serum and they did not grow anchorage independently in soft agar. Moreover, cells transfected with the NS3 serine protease and treated with the chymotrypsin inhibitors TPCK and PMSF (a serine protease inhibitor) lost their transforming feature. These results suggest that the NS3 serine protease of HCV is involved in cell transformation and that the ability to transform requires an active enzyme.
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PMID:Cell transformation induced by hepatitis C virus NS3 serine protease. 1126 29

The genes encoding alpha 1-antitrypsin (alpha 1AT, gene symbol P I) and corticosteroid-binding globulin (CBG) are part of a cluster of serine protease inhibitor (serpin) genes on human chromosome 14q32.1. Both genes are highly expressed in the liver and in cultured hepatoma cells, and the approximately 100-kb region around these genes contains an extensive array of expression-associated DNase I-hypersensitive sites (DHSs). Activation of human alpha 1AT and CBG transcription occurred when human chromosome 14 was transferred from nonexpressing cells to rat hepatoma cells. This activation event was accompanied by long-range chromatin reorganization of the entire region and the de novo formation of 17 expression-associated DHSs. Both gene activation and chromatin remodeling in hepatic cells required the liver-enriched transactivators hepatocyte nuclear factors-1 alpha and -4 (HNF-1 alpha and HNF-4). In this study, we tested whether ectopic expression of HNF-1 alpha and HNF-4 in nonexpressing cells could activate alpha 1AT and/or CBG transcription, and we monitored the chromatin structure of the locus in stably transfected fibroblasts. We report that both alpha 1AT and CBG mRNAs were expressed in fibroblast transfectants that stably expressed HNF-1 alpha and HNF-4, but expression was only approximately 1-10% of that observed in hepatic cells. Gene activation in these cells was accompanied by partial chromatin remodeling, as 6 of 17 expression-associated DHSs were formed. The potential implications of these results are discussed.
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PMID:Partial activation of gene activity and chromatin remodeling of the human 14q32.1 serpin gene cluster by HNF-1 alpha and HNF-4 in fibroblast microcell hybrids. 1158 88

In the human hepatic cell line, HepG2, apolipoprotein B100 (apoB100) degradation is increased by inhibiting lipid transfer mediated by the microsomal triglyceride transfer protein (MTP) and is predominantly accomplished by the ubiquitin-proteasome pathway. In the current study, we determined whether this degradative pathway was restricted to HepG2 cells or was of more general importance in hepatic apoB100 metabolism. Rat hepatoma McArdle RH7777 cells (McA), compared to HepG2 cells, secrete a large fraction of apoB100 associated with VLDL particles, as does the normal mammalian liver. In McA cells studied under basal conditions, the proteasome inhibitor lactacystin (LAC) increased apoB100 recovery, indicating that the role of the proteasome in apoB100 metabolism is not restricted to HepG2 cells. When apoB100 lipidation was blocked by an inhibitor of MTP (MTPI), recovery of cellular apoB100 was markedly reduced, but LAC was only partially ( approximately 50%) effective in reversing the induced degradation. This partial effectiveness of LAC may have represented either (1) incomplete inhibition by LAC of its preferred target, the chymotrypsin-like activity of the proteasome, (2) the presence of an apoB100 proteolytic activity of the proteasome resistant to LAC, or (3) a nonproteasomal proteolytic pathway of apoB100 degradation. By studying immunoisolated proteasomes and McA cells treated with LAC and/or MTPI and a variety of protease inhibitors, we determined that the proteasomal component of apoB100 degradation was entirely attributable to the chymotrypsin-like catalytic activity, but only accounted for part of apoB100 degradation induced by MTPI. The nonproteasomal apoB100 degradative pathway was nonlysosomal and resistant to E64d, DTT, and peptide aldehydes such as MG132 or ALLN but was partially sensitive to the serine protease inhibitor APMSF. Furthermore, when the protein trafficking inhibitor, brefeldin A, was used to block endoplasmic reticulum (ER) to Golgi transport in MTPI-treated McA cells, degradative activity resistant to LAC was increased, suggesting that the nonproteasomal pathway is associated with the ER.
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PMID:The inhibition of microsomal triglyceride transfer protein activity in rat hepatoma cells promotes proteasomal and nonproteasomal degradation of apoprotein b100. 1214 75

Chronic hepatitis C is a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Recent progress in the understanding of the molecular virology of hepatitis C has allowed the identification of novel antiviral targets. Moreover, in vitro and in vivo model systems have been developed that allow the systematic evaluation of new therapeutic strategies. Exciting results from proof-of-concept clinical studies have now been reported for a specific hepatitis C virus serine protease inhibitor. These and other novel antiviral strategies may complement existing therapeutic modalities in the future.
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PMID:Recent developments in target identification against hepatitis C virus. 1526 25

Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema. Severe chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma. The alpha-1 antitrypsin molecule is a serine protease inhibitor that is predominantly produced in the liver. Its most important physiologic functions are the protection of pulmonary tissue from aggressive proteolytic enzymes and regulation of pulmonary immune processes. Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis. Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease. A further option is substitution therapy with human alpha-1 antitrypsin. The targets of treatment are the prevention of the accelerated decline of pulmonary function, reduction of lung infections, and improvements in exercise capacity.
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PMID:Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. 1850 Dec 15

Pharmacological demethylation-based gene expression profile analysis is a useful tool to identify epigenetically silenced tumour suppressor genes. HGF activator inhibitor 2 (HAI-2), a serine protease inhibitor, has been identified as one of the candidate tumour suppressor genes in human hepatocellular carcinoma (HCC) with this technique. In this study, we aimed to characterise the epigenetic status and tumour suppressive function of HAI-2 in HCC. We validated that HAI-2 expression was either absent or low in most of the HCC cell lines tested, and 5-Aza-2'-deoxycytidine treatment significantly restored its expression in 9 (75%) of these 12 cell lines. HAI-2 was found to be frequently underexpressed in human HCCs (p < 0.001). With bisulphite DNA sequencing and methylation-specific PCR, we found that the promoter of the HAI-2 gene was frequently hypermethylated in both HCC cell lines and human HCCs. Ectopic expression of HAI-2 significantly inhibited cell migration and invasiveness of HCC cells in vitro and suppressed tumourigenicity in vivo. In addition, we also provided the first evidence that HAI-2 mediated its tumour suppressor function via the Kunitz domain 1 (KD-1), as KD-1 but not KD-2 inactivating mutant abolished its anti-tumour invasiveness in vitro. Our findings suggest that HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function.
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PMID:HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions. 1910 35


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