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)

Integrins are a superfamily of cell surface glycoproteins that promote cellular adhesion. The interaction of integrins with extracellular matrices such as fibronectin and vitronectin has been shown to be mediated through an arginine-glycine-aspartic acid (RGD) sequence within adhesive proteins. Triflavin, a 7.5-kDa cysteine-rich polypeptide purified from Trimeresurus flavoviridis snake venom, belongs to a family of RGD-containing peptides, termed disintegrins. Disintegrins have been isolated from the venom of various vipers and have been shown to be potent inhibitors of platelet aggregation. In this study, we found that human hepatoma cell adhesion to immobilized matrix proteins (i.e. fibronectin, collagen, laminin, and vitronectin) was differentially affected by various anti-integrin monoclonal antibodies (mAbs) (i.e., alpha3beta1, alpha5beta1, alpha6beta1, and alpha v beta3) as well as by the peptide GRGDS. Indirect flow cytometric analysis of hepatoma cells with anti-integrin mAbs demonstrated that alpha6beta1 was uniformly expressed at a high density, while alpha3beta1, and alpha5beta1 were moderately expressed and alpha v beta3 was expressed in small amounts on hepatoma cells, consistent with the results obtained from immunofluorescence microscopic analysis. When immobilized on plastic wells, triflavin promoted hepatoma cell attachment; this cell attachment was inhibited by either GRGDS or mAbs against integrins alpha3beta1, alpha5beta1 and alpha v beta3). In addition, the binding of FITC-conjugated triflavin to hepatoma cells was inhibited by GRGDS, anti-alpha3beta1, antialpha5beta1, and anti-alpha v beta3 mAbs. Among these mAbs, anti-alpha5beta1 exerted the most pronounced inhibitory effect (>70%) on the binding of triflavin to hepatoma cells. Taken together, these results suggest that triflavin binds via its RGD sequence to multiple integrin receptors (i.e., alpha5beta1, alpha3beta1, and alpha v beta3) expressed on the surface of hepatoma cells, resulting in inhibition of hepatoma cell adhesion to extracellular matrices (i.e., fibronectin and vitronectin).
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PMID:Triflavin, an Arg-Gly-Asp-containing peptide, inhibits the adhesion of tumor cells to matrix proteins via binding to multiple integrin receptors expressed on human hepatoma cells. 882 Aug 26

The conformation and degree of multimerization of vitronectin (Vn) appears to be of critical importance for its functions, but little is known about the underlying mechanisms that control Vn multimerization. We report that Vn secreted by cultured hepatoma cells is present as a mixture of monomeric and multimeric forms. A single protein of Mr 45,000 co-purified with hepatoma cell-derived Vn, which was immunologically identified as type 1 plasminogen activator inhibitor (PAI-1). The possibility that PAI-1 may modulate Vn multimerization was investigated. The addition of active PAI-1 to unfractionated plasma containing Vn monomers resulted in the formation of covalently and noncovalently associated Vn multimers and expression of conformationally sensitive epitopes. In contrast, inactive forms of PAI-1 did not efficiently induce Vn multimerization and conformational change. Gel filtration analysis revealed that Vn remained multimeric after dissociation from PAI-1. Vn multimers were also assembled using purified monomeric Vn and PAI-1, suggesting that a plasma cofactor was not required to induce Vn multimerization. This study provides insights into physiological mechanism responsible for the generation of homomultimeric Vn, a multimeric form of Vn that is not in complex with other proteins and which expresses a functional repertoire distinct from that of plasma Vn.
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PMID:Type 1 plasminogen activator inhibitor induces multimerization of plasma vitronectin. A suggested mechanism for the generation of the tissue form of vitronectin in vivo. 893 96

Plasma collagen-binding vitronectin was assayed in 62 patients with chronic liver disease and 14 healthy control subjects. It was measured by an enzyme immunoassay using type I collagen and monoclonal antibody to vitronectin before and after treatment with heparin or dextran sulfate in vitro. The pretreatment level of plasma collagen-binding vitronectin (mean +/- S.E.M.) was 5.5 +/- 0.5 micrograms/ml in the controls, 8.2 +/- 0.3 micrograms/ml in chronic persistent hepatitis, 8.3 +/- 0.7 micrograms/ml in chronic active hepatitis, 7.9 +/- 0.7 micrograms/ml in liver cirrhosis, and 8.2 +/- 0.5 micrograms/ml in hepatocellular carcinoma with cirrhosis. After treatment with heparin, the percent collagen-binding vitronectin to total vitronectin was 20.6 +/- 2.0% in the controls, 24.7 +/- 4.1% in chronic persistent hepatitis, 28.6 +/- 2.5% in chronic active hepatitis, 42.6 +/- 4.5% in liver cirrhosis, and 31.8 +/- 2.3% in hepatocellular carcinoma. All percents were significantly increased compared to the pretreatment percent. The same pattern was also found after dextran sulfate treatment. Compared to that in the pretreatment state, the collagen-binding vitronectin after these treatments was more closely correlated with the serum levels of 7S collagen and hyaluronic acid. These results suggest that the collagen-binding activity of vitronectin may play an important role in the progression of liver disease and/or fibrosis through its activation with some glycosaminoglycans.
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PMID:Plasma collagen-binding vitronectin activated by heparin and dextran sulfate in chronic liver disease. 938 91

Vitronectin in a cell-adhesion molecule whose expression is temporally and spatially regulated in vivo, but whose regulatory mechanism of transcription is unknown. In this study, we characterized the mouse vitronectin gene promoter. Luciferase expression vectors cloned the successive 5'- or 3'-deletions of the 5'-flanking region upstream of the luciferase gene and were transfected into the human hepatoma cell line HepG2. The assay of luciferase activity in the transfected cells revealed that a 38 base pair (bp)-element (positions +3 to +40) displays promoter activity. A consensus sequence consisting of a TATA box and initiator is shown around the transcription initiation site of the mouse vetronectin gene, but the GC box is not shown. Site-directed or deleted mutagenesis against a consensus sequence of TATA box and initiator could not abolish the promoter activity. These results induce that the putative TATA box and initiator are not involved in the promoter activity, and that the vitronectin promoter lacks the TATA box, initiator and GC box. To characterize trans-acting factors involved in promoter activity, a DNA fragment (position -74 to +95) was subjected to gel shift assay using nuclear proteins extracted from HepG2 cells. One shifted band was detected by the gel shift assay, suggesting that a nuclear protein binds to the promoter region. Results of the DNase I foot printing assay and gel shift assay demonstrate that the nuclear proteins can bind to the 38 bp-element, which has promoter activity. The nuclear protein is a putative trans-acting factor involved in transcription initiation.
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PMID:TATA-less mouse vitronectin gene promoter: characterization of the transcriptional regulatory elements and a nuclear protein binding site on the promoter. 963 27

The functional role of the hepatitis B virus (HBV) pre-S region for assembly and appearance of the virus is not completely understood. In this study, 3 natural-occurring mutants were investigated. Three mutants of the pre-S region-a point mutation in the CCAAT box (MUT1), a 6-bp deletion (MUT2) 3' of the CCAAT box, and a 153-bp deletion (MUT3) in the preS2 domain-were cloned alone or in combinations in replication-competent HBV plasmids and transfected in hepatoma cells. The impact on HBV assembly and appearance was studied by Northern Blot, primer extension analysis, immunofluorescence studies, enzyme-linked immunosorbent assay, and electron microscopy. An inversed ratio of pre-S/S mRNA transcripts compared with wild-type (wt) HBV was found when either MUT1 or -2 were included into the plasmid. Intracellular localization with both mutants showed retention of large S-protein in the endoplasmic reticulum and nuclear accumulation of core protein. The extracellular amount of S-protein was reduced with MUT1 and -2 or combinations in which 1 of the mutants was included. However, the extracellular appearance of viral products was comparable with wtHBV. In contrast, MUT3 showed major changes. Virion-like particles had a fried-egg, and filaments a screw-like appearance. The S-promoter mutations MUT1 and MUT2 correlated with viral retention. MUT3 leads to malformed viral particles. Therefore, different regions in the pre-S domain are essential to determine the intracellular localization and extracellular appearance of HBV, and might contribute to the prognosis of chronic HBV infection.
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PMID:The pre-S region determines the intracellular localization and appearance of hepatitis B virus. 1042 62

Eight cDNAs encoding galectin 4 (Gal-4), UGT2B4 (UDP-glucuronosyltransferase), ribosomal phosphoprotein P0 (rpP0), dek, insulin-like growth factor binding protein (IGFBP) 1, vitronectin, retinoic acid-induced gene E (RIG-E), and CYP3A4 (cytochrome P450 nifedipine oxidase) were identified as differentially expressed genes between human hepatocellular carcinoma (HCC) and matched nontumorous liver tissues. Higher levels of UGT2B4, rpP0, dek, vitronectin, Gal-4, and IGFBP-1 mRNAs combined with a lower level of RIG-E mRNA were observed in at least four of five primary HCCs compared to matched nontumorous liver tissues. Furthermore, a pathological study suggested that the levels of UGT2B4, rpP0, dek, and vitronectin increased and the level of RIG-E decreased with the histological grading. On the other hand, the expression of CYP3A4 mRNA and CYP3A7 (P-450 Fla) mRNA, a transcript found in the fetus and highly homologous to CYP3A4, was higher in all nontumorous liver and some of the carcinoma tissues from five HCC patients, whereas it was significantly lower in normal liver tissues from two non-HCC patients. The examination using HCC cell lines HuH-7 and HepG2 under different growth conditions suggested that the expression of dek mRNA was growth-associated. In contrast, the expression of Gal-4, UGT2B4, IGFBP-1, and RIG-E mRNAs was regulated in a cell density-dependent manner: the levels of Gal-4, UGT2B4, and IGFBP-1 were undetectably low, whereas the level of RIG-E was high in rapidly proliferating, subconfluent HCC cells in 10% serum; however, the expression levels were reversed in dense, overcrowded cultures. In addition, IGFBP-1 and Gal-4 mRNAs were also induced by reducing the serum concentration to 0.1%. We also demonstrated that sodium butyrate, an inducer of differentiation, up-regulated and down-regulated RIG-E and dek mRNAs, respectively, in a dose-dependent manner in HuH-7 cells, supporting, in part, our pathological observation. In summary, therefore, high expression of Gal-4, UGT2B4, rpP0, dek, IGFBP-1, and vitronectin, together with low expression of RIG-E, was correlated with the malignant potential of HCC. CYP3A4 and CYP3A7 could be induced in HCC-bearing livers. These transcripts are differentially regulated depending on cell-cell contact, serum growth factors, growth and differentiation status, and/or other mechanisms in premalignant and malignant liver cells.
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PMID:Identification and characterization of genes associated with human hepatocellular carcinogenesis. 1051 13

Our previous report demonstrated that all-trans-retinoic acid (ATRA) induces detachment and death under serum starvation in several human tumor cell lines. In this study, we examined the influence of cell-extracellular matrix interaction on the ability of ATRA to induce apoptosis. Plating of human hepatoma Hep3B cells onto poly-hydroxyethylmethacrylate-coated plates in the absence of serum resulted in the acceleration of ATRA-induced apoptosis. In contrast, ATRA-induced apoptosis was significantly suppressed by plating cells onto Matrigel-coated plates but not suppressed by culturing onto collagen-, laminin-, vitronectin-, or fibronectin-coated plates. Exogenously added soluble collagen, laminin, fibronectin, vitronectin or Matrigel failed to suppress ATRA-induced apoptosis. Results from the adhesion assay indicated that the cell attachment to fibronectin was significantly inhibited by ATRA. Treatment with perturbing antibody against integrin alpha5 or beta1 subunits resulted in promotion of ATRA-induced apoptosis. Moreover, the proteolytic cleavage of alpha5beta1 integrin and focal adhesion kinase (FAK) proteins is linked to the early phase of the ATRA-induced apoptotic process. Furthermore, ATRA-induced detachment, death, and cleavage of alpha5beta1 integrin and FAK were drastically suppressed by plating cells onto Matrigel-coated plates. These findings provide evidence that abrogation of cell adhesion, through proteolysis of alpha5beta1 integrin and FAK, is closely linked to ATRA-induced apoptosis in Hep3B cells.
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PMID:Proteolysis of integrin alpha5 and beta1 subunits involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells. 1136 41

There is increasing evidence that certain pathogenic hepatitis B virus (HBV) variants may play a role in the pathogenesis of fulminant hepatitis (FHB). Recently, we isolated from a patient with fulminant recurrent hepatitis B after liver transplantation variants with enhanced replication competence and a possible defect in viral particle secretion. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequences, and to identify the responsible viral mutations. The variant genomes and appropriate wild-type/variant hybrid genomes were functionally characterized after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of full-length genomes showed a block in viral particle secretion. This was caused by a combination of amino acid changes in the S-protein including the mutation G145R frequently emerging after hyperimmunoglobulin treatment. The mutations induced retention of the surface proteins in an endoplasmic reticulum (ER)-like compartment, but no intracellular accumulation. These data provide evidence for the in vivo existence of a dominant HBV population with a severe defect in viral particle secretion caused by mutations in the S-gene. This viral phenotype in combination with the enhanced replication competence may have contributed to the fulminant clinical course of the infection.
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PMID:A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis. 1148 31

The mouse vitronectin promoter has two consensus sequences of the Foxa/hepatocyte nuclear factor (HNF) 3-binding site (from -34 to -25, site A, and +15 to +26 base pairs (bp), site B). Site-directed mutagenesis of site B inhibited binding of nuclear proteins from mouse neuroblastoma Neuro2a and reduced the promoter activity to 4.6% in a 101-bp fragment (from -48 to +53 bp) in Neuro2a cells. The nuclear proteins of site B were identified as the Foxa1/HNF3alpha and Foxa2/HNF3beta proteins by supershift assay. Next, we examined site A. Mutation of site A in Neuro2a cells did not affect the promoter activity, and binding of nuclear proteins was not detected. Overexpression of Foxa1 or Foxa2 protein activated the mutated site B promoter, but failed to activate the sites A and B double-mutated promoter in Neuro2a cells, indicating that site A is a potential transcription regulatory site. Recombinant Foxa1 and Foxa2 proteins and nuclear extract from mouse liver bound not only to site B, but also to site A. In human hepatoma HepG2 cells, mutation of sites A and B decreased the promoter activity to 82% and 38%, respectively, in the wild promoter, and double mutation of sites A and B decreased the wild promoter activity to 5%, indicating that sites A and B contribute to the promoter activity in HepG2 cells. These results demonstrate that the two Foxa-binding sites regulate the vitronectin promoter activity in cell type-dependent manner.
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PMID:Cell-type dependency of two Foxa/HNF3 sites in the regulation of vitronectin promoter activity. 1199

The expression of alpha V integrins by neoplastic cells contributes to the promotion of local invasion and metastasis. The most characteristic extracellular ligands of alpha V integrins are vitronectin and fibronectin. Hepatocytes are the main source of vitronectin, and the capacity to synthesize and secrete vitronectin is usually retained in hepatocellular carcinoma. The aim of this study was to explore the expression, regulation, and functional role of alpha V integrins in hepatocellular carcinoma. We first analyzed the expression of alpha V integrins and their ligands fibronectin and vitronectin in 80 cases of hepatocellular carcinoma. alpha V integrin chain was detected in 44 cases and vitronectin in 50. Twenty-four of the 44 alpha V-positive tumors contained large amounts of vitronectin. These cases presented more frequently with adverse histoprognostic factors, including infiltrative growth pattern (62.5%), lack of capsule (71%), presence of capsular invasion (57%), and satellite nodules (50%). We then used HepG2 and Hep3B cell lines as in vitro models to study alpha V integrin regulation and function. HepG2 and Hep3B cells expressed alpha V integrin chain and used alpha V beta 1 and alpha V beta 5 for adhesion and migration on vitronectin. Tumor necrosis factor (TNF) alpha and transforming growth factor (TGF) beta significantly increased the expression levels of alpha V integrins and stimulated the adhesion and migration of both HepG2 and Hep3B cell lines on vitronectin. The effects of growth factors on cell adhesion and migration were reproduced by incubation with conditioned medium from rat liver myofibroblasts. In conclusion, our results support the existence of an alpha V integrin/vitronectin connection in hepatocellular carcinoma and suggest that this connection may be an adverse prognostic factor.
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PMID:Expression, regulation, and function of alpha V integrins in hepatocellular carcinoma: an in vivo and in vitro study. 1214 51


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