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)

Expression of mucin core protein of mammary type (MUC-1 core protein) was investigated in primary hepatic carcinoma (25 cases of cholangiocarcinoma, 15 cases of combined hepatocellular-cholangiocellular carcinoma and 18 cases of hepatocellular carcinoma) with monoclonal antibody DF3 and a standard avidinbiotin complex method. MUC-1 core protein was almost always expressed in cholangiocarcinoma and in the cholangiocarcinoma area of hepatocellular-cholangio-cellular carcinoma to a varied degree, whereas such expression was virtually absent in hepatocellular carcinoma and the hepatocellular carcinoma areas of hepatocellular-cholangiocellular carcinoma. Nonneoplastic intrahepatic biliary epithelium, as well as hepatocytes, was virtually negative for this protein. In well-differentiated cholangiocarcinoma, this protein tended to be expressed on luminal surfaces, whereas poorly differentiated cholangiocarcinoma showed cell membranous or diffuse cytoplasmic staining patterns. Double staining with Alcian blue (pH 2.5) and immunostaining for MUC-1 core protein showed that although some parts of cancerous areas were positive for both stains, most cancerous areas were only positive for one. Alcian blue--positive areas were dominant over MUC-1 core protein--expressing areas in well-differentiated cholangiocarcinoma, whereas the reverse was the case in poorly differentiated cholangiocarcinomas and also in cholangiocarcinoma areas of hepatocellular-cholangiocellular carcinoma. This study is the first report to document that cholangiocarcinoma and cholangiocarcinoma areas of hepatocellular-cholangiocellular carcinoma express MUC-1 core protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of mucin core protein of mammary type in primary liver cancer. 752 72

Our aim was to investigate the existence of an association between B cell responsiveness to hepatitis C virus (HCV) core protein and progression of liver disease. In fact, the persistence of HCV infection is permitted by avoidance of viral clearance, despite chronic inflammation in the liver; this process ends with the development of hepatocellular carcinoma in many patients. On the basis of computerized prediction of antigenicity of the genomic sequence of HCV core protein, three 15-mer peptides (named Q15V, R15P, and G15V) were synthesized to be used as antigens in an enzyme immunoassay. Sera from 97 patients (65 males and 32 females) were tested: 43 patients had mild chronic liver disease (steatofibrosis, chronic persistent, or chronic active hepatitis) and 54 had cirrhosis, which was complicated by hepatocellular carcinoma (HCC) in 19. Seventy-six patients were positive to anti-HCV testing by second generation ELISA and 21 were negative. Rates of positivity for synthetic peptides in anti-HCV-positive versus anti-HCV negative patients were as follows: 53 of 76 and 0 of 21 for anti-Q15V; 41 of 76 and 0 of 21 for R15P; and 67 of 76 and 2 of 21 for G15V. Rates of positivity to anti-Q15V and anti-G15V were similar among diagnostic groups (Pearson's chi 2, 1.97, P > 0.10 and 0.45, P > 0.10), whereas anti-R15P antibodies were detected at a significantly lower rate in patients with HCC (2/13) in comparison to mild chronic liver disease (22/35) and cirrhosis (17/28) (Pearson's chi 2, 9.42, P < 0.01). We conclude that anti-R15P antibodies are uncommon in anti-HCV-positive patients with HCC. During the course of chronic HCV infection, anti-R15P testing might help to identify a subgroup at higher risk to develop HCC.
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PMID:Reactivity to B cell epitopes within hepatitis C virus core protein and hepatocellular carcinoma. 752 37

Despite the extensive molecular information on serum-derived human hepatitis B viruses (HBV), liver-derived replicative HBV genomes have remained largely uninvestigated. We have examined the sequences of the entire core antigen (nucleocapsid) of liver-derived HBVs in 15 different hepatoma patients. Bona fide mutations, rather than subtype polymorphism, have been identified based on the high-frequency occurrence of structural differences from wild type at the highly evolutionarily conserved positions, instead of at the positions known to contain genetic heterogeneity among different isolates from different geographic locations. The distribution of these naturally occurring mutations of HBV core gene appears to be nonrandom and is found predominantly within three major (I, IV, and V) and four minor domains (II, III, VI, and VII). In general, domain IV mutations correlate with domain V mutations. The replicative HBV DNAs tend to accumulate a higher number of mutated core domains than the integrated HBV DNAs. At the domain level, there is no significant difference in HBV core mutation frequencies between the liver tumors and the adjacent nontumorous livers. Strikingly, domains I, III, and V coincide with three major known T cell epitopes within the core protein in acute and chronic hepatitis B patients. Furthermore, these domains coincide with HLA class II-restricted T cell epitopes, rather than with the conventional HLA class I-restricted epitopes of cytotoxic T lymphocytes. Our results support the hypothesis that HBV core antigen variants can accomplish immunoevasion via accumulated escape mutations. In addition, they also provide a potential molecular explanation for the maintenance of persistent infection of human hepatitis B virus in chronic carriers.
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PMID:Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II-restricted T cell epitopes. 754 53

Hepatitis B virus core protein (antigen) is an important serologic marker of hepatitis B virus infection. This protein is found in the cytoplasm or the nuclei, or both, of infected hepatocytes. A nuclear localization signal has previously been identified in the core protein sequence. This signal overlaps three repeated SPRRR motifs. In this report, we demonstrate that substitution of all of the serine residues in these three SPRRR motifs with alanine can prevent almost entirely the phosphorylation of the core protein in Huh-7 hepatoma cells, enhance nuclear localization of the core protein in both Huh-7 and nonhepatic cells, and abolish cell cycle regulation of nuclear localization of the core protein. Since the three core protein mutants which retained only one serine residue of each of the three SPRRR motifs could be phosphorylated to similar degrees, these three serine residues likely could serve as the acceptor sites for phosphorylation with equal efficiency. These results, together with the observation that the three SPRRR motifs overlap the nuclear localization signal of the core protein, raise the possibility that nuclear localization of the core protein is negatively regulated by phosphorylation of the serine residues in the SPRRR motifs.
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PMID:Phosphorylation and nuclear localization of the hepatitis B virus core protein: significance of serine in the three repeated SPRRR motifs. 781 79

We previously demonstrated that the core protein of hepatitis C virus (HCV) can suppress gene expression and replication of hepatitis B virus (HBV) in a human hepatoma cell line (HuH-7). In this study, we have characterized the phosphorylation property of HCV core protein and examined the effect of phosphorylation on its suppressive activity of HBV. Our results indicated that both the full-length HCV core protein (22 kDa) and its processed or degraded forms (14 to 18 kDa) were phosphorylated in insect cells. As demonstrated by using the glutathione S-transferase fusion protein expression system and in vitro transcription and translation system, the phosphorylation of HCV core protein was carried out by protein kinase A (PKA) and protein kinase C (PKC) in vitro. In both kinase reactions, it was determined that the phosphorylated amino acid was a serine residue. The potential phosphorylated sites in core protein were identified as residues Ser-53 and Ser-116 for PKA and Ser-53 and Ser-99 for PKC. Comparison of the phosphorylation intensities of the wild type and Ser mutants suggested that Ser-99 and Ser-116 were the major phosphorylation sites for PKC and PKA, respectively. The phosphorylation of Ser-99 and Ser-116, but not Ser-53, in HCV core protein was essential for the suppressive activity of HCV core protein on HBV gene expression and replication in HuH-7 cells. Mutation of the former two serine residues to alanine or aspartate residues led to a drastic loss of the inhibitory effects of HCV core protein on HBV gene expression (both transcription and antigen production) and pregenomic RNA encapsidation, as well as the release of HBV virus particles. In contrast, the Ser-53 mutant conferred the same level of suppressive activity as the wild type did. This property is in accordance with the observation that Ser-99 and Ser-116 are the predominant phosphorylation sites in the HCV core construct. All serine mutants (including those with mutations in PKA, PKC, and both kinase recognition sites) of HCV core protein retained the ability to translocate into the nucleus. Furthermore, wild-type HCV core protein diminished its suppressive activity when cells were treated with PKA or PKC inhibitor. In conclusion, HCV core protein is a phospho-protein and in HuH-7 cells, its trans suppression of HBV gene expression and replication is positively regulated by PKA and PKC. The role of phosphorylation in the control of trans-suppressive activity cannot be reproduced by introducing an acidic residue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of the trans-suppression activity of hepatitis C virus core protein by phosphorylation. 781 94

We have generated and functionally characterized dominant negative core protein variants of the hepadnaviruses to determine their effects on "wild type" viral replication. Plasmids expressing these constructs were introduced into hepatoma cell lines by transient transfection and effects on wild type woodchuck hepatitis virus (WHV) and hepatitis B virus (HBV) replication were evaluated by Southern blot analysis of purified viral core particles. WHV and HBV constructs expressing a truncated core protein fused in frame with the C-terminus of the small surface protein were found to inhibit viral replication by 90-95% due to disruption of the viral nucleocapsid assembly process and preventing encapsidation of pregenomic RNA. The antiviral effects were found to be specific for the targeted virus. These results demonstrate that mutants of hepadnaviral core protein may represent a novel class of antiviral agents.
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PMID:Characterization of hepatitis B virus core mutants that inhibit viral replication. 797 6

Hepatitis B and C viruses (HBV and HCV, respectively) are associated with acute and chronic liver diseases and hepatocellular carcinoma. To elucidate the molecular status of superinfection with these two hepatitis viruses, we cotransfected the full-length or truncated version of HCV structural genes (core and envelope 1) together with the cloned HBV DNA into a human hepatoma cell line (HuH-7). Expression of HBV-specific major transcripts (3.5 and 2.1 kb), as well as HBV antigens (hepatitis B surface antigen and hepatitis B e and core antigens), was reduced about two- to fourfold by the presence of the HCV structural genes. In addition, the secretion of HBV viral particles, including the viral nucleocapsid and mature virion, was drastically suppressed about 20-fold. Analysis of the intracellular HBV core protein-associated nucleic acid indicated that the encapsidated HBV pregenomic RNA was similarly reduced about 14-fold. Deletion analysis of the HCV structural genes demonstrated that the core gene alone or the fragment containing the core protein's N-terminal 122 amino acid residues conferred the same level of suppressive activity as the full-length structural genes. By indirect immunofluorescence, we found that the core protein of HCV was located in the cytoplasm of transfected HuH-7 cells at day 3 posttransfection and was targeted to the nucleus at day 6. Thus, the kinetics of the suppressive effect exerted by HCV constructs matched the timing of core protein entrance into the nucleus. Our results substantiate the clinical finding that HBV markers are suppressed by superinfection with HCV and further imply that this inhibitory effect may occur in the processes of transcription and encapsidation of HBV pregenomic RNA and may be mediated by the core protein of HCV. The deduced amino acid sequence of the HCV core protein has revealed that it is a basic protein which contains a putative DNA-binding motif (SPRG), as well as triplicate nuclear localization signals and several putative protein kinase A and C recognition sites. These characteristics imply that the HCV core protein can also function as a gene-regulatory protein.
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PMID:Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. 839 58

The Hepatitis B virus core promoter regulates the expression of the core protein, the precore protein, and the viral DNA polymerase. This promoter is transactivated by HNF4, a liver-enriched transcription factor, through an HNF4 binding site located upstream of the core promoter. The transactivation activity of HNF4 on the core promoter is antagonized by a negative regulatory element (NRE) located upstream of the HNF4 binding site. While the NRE can effectively antagonize HNF4 to suppress the core promoter in HeLa cervical carcinoma cells, it has only a marginal suppressing activity on the core promoter in Huh7 hepatoma cells. By performing deletion-mapping experiments, we have found that the NRE contains at least three independent subregions named NRE alpha, NRE beta, and NRE gamma. Each of these three subregions possesses a weak suppressing activity, but together they generate a strong synergistic suppressing effect on the core promoter. The NRE gamma subregion is active in both HeLa and Huh7 cells and is bound by a protein factor slightly less than 130 kDa in molecular mass. The NRE alpha and NRE beta subregions are active in HeLa cells but not in Huh7 cells. Thus, the marginal suppressing effect of the NRE observed in Huh7 cells was mostly due to the activity of the NRE gamma subregion. No clear protein factor binding sites could be identified in the NRE alpha and NRE beta subregions when the HeLa nuclear extract was used for the DNaseI-footprinting analysis, indicating weak or no protein association with these two subregions in this cell type. However, extensive protein factor binding sites could be identified throughout the sequences of these two subregions when the Huh7 nuclear extract was used for the analysis. These results indicate that a different set of protein factors binds to the NRE alpha and NRE beta subregions in Huh7 cells and may account for the inactivity of these two subregions in this cell type. Thus, our results indicate that the cell type-dependent activity of the NRE is due to differential regulation of the activities of the NRE alpha and NRE beta subregions by the cell types. This regulation is most likely mediated by cell type-dependent protein factors.
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PMID:Cell type-dependent regulation of the activity of the negative regulatory element of the hepatitis B virus core promoter. 852 15

The genomic region encoding the hepatitis C virus (HCV) core protein was cloned into a mammalian expression vector to study its role on the transcriptional regulation of cellular proto-oncogene and viral promoters. Using a transient transfection assay in human hepatocellular carcinoma (HepG2) cells, we demonstrate that the HCV core protein activates the human c-myc, Rous sarcoma virus long terminal repeat (LTR), and simian virus 40 (SV40) early promoters; and suppresses the c-fos promoter and human immunodeficiency virus type 1 (HIV-1) LTR activity. The transcriptional regulation of cellular proto-oncogenes by the HCV core protein suggests possible involvement of the core protein in the deregulation of normal hepatocyte growth and hepatocarcinogenesis.
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PMID:Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein. 853 58

We have previously demonstrated that hepatitis C virus (HCV) core protein regulates cellular protooncogenes at the transcriptional level; this observation implicates core protein in the alteration of normal hepatocyte growth. In the present study, the transforming potential of the HCV core gene was investigated by using primary rat embryo fibroblast (REF) cells which were transfected with or without cooperative oncogenes. Integration of the HCV core gene resulted in expression of the viral protein in REF stable transformants. REF cells cotransfected with HCV core and H-ras genes became transformed and exhibited rapid proliferation, anchor-independent growth, and tumor formation in athymic nude mice. Results from these studies suggest that the core protein plays an important role in the regulation of HCV-infected cell growth and in the transformation to tumorigenic phenotype. These observations suggest a possible mechanism for this viral protein in the pathogenesis of hepatocellular carcinoma in HCV-infected humans.
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PMID:Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. 867 67

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