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)

Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.
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PMID:Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. 1214 99

The increased proliferation rate of hepatocytes is one of the major risk factors for the development of hepatocellular carcinoma. In this study, we investigated the mechanism by which hepatitis C virus (HCV) core protein represses transcription of the universal cyclin-dependent kinase inhibitor p21 gene in murine fibroblast NIH 3T3 cells. From the transient reporter assays of p21 promoter, we found that the TGF-beta-responsive element (TbetaRE) located between -83 and -74 of the p21 promoter is responsible for the effect. The TGF-beta-induced p21 promoter activity was specifically decreased by HCV core protein and in the presence of the inhibitory Smad7 the repression effect was almost completely abolished. Furthermore, HCV core protein stimulated the growth rate of NIH 3T3 cells and could overcome growth arrest by TGF-beta but not by butyrate, suggesting that HCV core protein stimulates cell cycle progression by repressing p21 transcription through a TGF-beta pathway.
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PMID:Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-beta pathway. 1218 67

The signal transducer and activator of transcription (STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis. However, cause of the persistent activation of STAT3 in human tumor cells is largely unknown. The hepatitis C virus (HCV) is a major etiological agent of non-A and non-B hepatitis, and chronic infection by HCV is associated with development of liver cirrhosis and hepatocellular carcinoma. HCV core protein is proposed to be responsible for the virus-induced transformation. We now report that HCV core protein directly interacts with and activates STAT3 through phosphorylation of the critical tyrosine residue. Activation of STAT3 by the HCV core in NIH-3T3 cells resulted in rapid proliferation and up-regulation of Bcl-XL and cyclin-D1. Additional expression of STAT3 in HCV core-expressing cells resulted in anchorage-independent growth and tumorigenesis. We propose that the HCV core protein cooperates with STAT3, which leads to cellular transformation.
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PMID:Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. 1220 79

The core protein of hepatitis C virus (HCV) has been implicated in hepatocarcinogenesis. In order to determine whether there is a correlation between mutations of the core protein and the development of hepatocellular carcinoma (HCC), the core protein-coding sequence of the viral genome of HCV subtype 1b (HCV-1b) obtained from patients with and without HCC was analyzed. We found that 12 (40.0%) of 30 HCV-1b isolates from patients with HCC but none of 29 isolates from patients without HCC had a point mutation(s) in an N-terminal region of 20 residues. Similarly, 10 (33.3%) of 30 isolates from patients with HCC had mutations in a limited region between residues 141 and 160, whereas only 2 (6.9%) of 29 isolates from patients without HCC did. The differences between the two groups were statistically significant. The mutations were found in isolates from both cancerous and adjacent noncancerous tissues of patients with HCC, suggesting that the mutations were present before the development of HCC. The other regions of the core protein of some isolates also had mutations, but no significant difference was observed between isolates from patients with HCC and those from patients without HCC. The F protein, a frameshift product that is still hypothetical for HCV-1b strains, showed more sequence diversity than the core protein among the isolates analyzed, but there were no significant differences in the mutation rates or positions between isolates from patients with HCC and isolates from patients without HCC, except for a short N-terminal sequence of approximately 11 residues that is shared with the core protein.
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PMID:Comparative sequence analysis of the core protein and its frameshift product, the F protein, of hepatitis C virus subtype 1b strains obtained from patients with and without hepatocellular carcinoma. 1235 56

To further investigate the functions of proteins encoded by C open reading frame of hepatitis B virus (HBV) in HBV infectious cycle, cell lines expressing these proteins were established. The DNA fragments encoding 25 000, 22 000 precore-core and 21 000 core protein respectively were amplified from plasmid pCP10 which contained HBV genome, and inserted into a eukaryotic expression vector pcDNA-3, and then transfected into hepatoma cell line HepG2. The transformants were selected with neomycin, and three isolated colonies expressing precore or core proteins were obtained stably, which were demonstrated by immunohistochemistry and Western blotting analysis.
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PMID:[Expression of precore and core proteins of hepatitis B virus in human hepatoma cell line]. 1239 Aug 22

Mutations of human hepatitis B virus (HBV) occur frequently within the capsid (core) protein in natural infections. The most frequent mutation of the core protein in HBV from Southeast Asia occurs at amino acid 97, changing an isoleucine (I) to a leucine (L). In our systematic study of virus-host interactions, we have examined the replication efficiency of a site-directed mutant, I97L, and its parental wild-type HBV in several different hepatoma cell lines. Interestingly, we found that this capsid variant replicated in human Huh7 hepatoma cells approximately 4.8-fold better than its parental wild-type HBV. A similar phenomenon was observed in another hepatoma cell line, J3. In addition, the level of encapsidated RNA pregenome in mutant I97L was about 5.7-fold higher than that of the wild-type HBV in Huh7 cells. Unlike Huh7 cells, no significant difference in viral DNA replication between the same I97L mutant and its parental wild-type HBV was observed in HepG2, a human hepatoblastoma cell line. This finding of a profound replication advantage for mutant I97L in Huh7 and J3 cells but not in HepG2 cells may have important implications for the emergence of this mutant in chronic HBV carriers. We speculate here that the mutation confers a host factor-independent growth advantage for the survival of HBV variants in gradually dedifferentiating hepatocytes and thus helps prolong viral persistence.
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PMID:Replication advantage and host factor-independent phenotypes attributable to a common naturally occurring capsid mutation (I97L) in human hepatitis B virus. 1241 48

Hepatitis C virus (HCV) is a major causative agent for chronic liver diseases leading to hepatocellular carcinoma (HCC) and has also been suggested to be a possible etiologic factor for different lymphoproliferative diseases, including mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (NHL). To understand the roles of HCV core protein in the pathogenesis of HCV related diseases, we produced two lines of the transgenic mice (HC82310 and HC9053) that express the HCV core transgene. One of the lines, HC9053, developed malignant lymphoma (ML, follicular center cell type) with a high frequency (80%) at the ages over 20 months. Hepatocellular adenoma was also observed in this line of transgenic mouse. We demonstrated expression of HCV core protein and mRNA in the liver of transgenic mice, and also detected the core mRNA in the enlarged lymph nodes of the transgenic mice which developed ML. These results suggest that the core protein may play an important role in the development of ML, and that the HC9053 transgenic mice provide suitable models for understanding the mechanism of HCV-related lymphoproliferative diseases.
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PMID:Expression of hepatitis C virus core protein associated with malignant lymphoma in transgenic mice. 1249 92

Hepatitis C virus (HCV) infection often leads to the development of hepatocellular carcinoma (HCC), but its molecular mechanism has not been clearly elucidated. Previously, transgenic mice constitutively expressing HCV core protein have been shown to develop HCC, suggesting a pivotal role of the core protein in hepatocarcinogenesis. Here, we analyzed the expression of cytokines associated with a variety of cellular processes, including cell proliferation, in the mouse model for HCV-associated HCC to define the molecular events prior to oncogenesis. The expression of tumor necrosis factor-alpha and interleukin-1beta was increased at both protein and mRNA levels. In addition, the activities of c-Jun N-terminal kinase and activator protein-1 (AP-1), downstream effectors, were enhanced, while IkappaB kinase or nuclear factor-kappaB activities were not enhanced. Thus, the altered in vivo expression of cytokines with AP-1 activation in consequence to the core protein expression may contribute to hepatocarcinogenesis in persistent HCV infection.
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PMID:Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein. 1250 80

Targeting therapeutic genes to the liver is essential to improve gene therapy protocols of hepatic diseases and of some hereditary disorders. Transcriptional targeting can be achieved using liver-specific promoters. In this study we have made chimeric constructs combining promoter and enhancer regions of the albumin, alpha 1-antitrypsin, hepatitis B virus core protein, and hemopexin genes. Tissue specificity, activity, and length of gene expression driven from these chimeric regulatory sequences have been analyzed in cultured cells from hepatic and nonhepatic origin as well as in mice livers and other organs. We have identified a collection of liver-specific promoters whose activities range from twofold to less than 1% of the CMV promoter in human hepatoma cells. We found that the best liver specificity was attained when both enhancer and promoter sequences of hepatic genes were combined. In vivo studies were performed to analyze promoter function during a period of 50 days after gene transfer to the mouse liver. We found that among the various chimeric constructs tested in this work, the alpha1-antitrypsin promoter alone or linked to the albumin or hepatitis B enhancers is the most potent in directing stable gene expression in liver cells.
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PMID:In vitro and in vivo comparative study of chimeric liver-specific promoters. 1266 33

Hepatitis B virus (HBV) is a causative agent of chronic and acute hepatitis, and is associated with the development of hepatocellular carcinoma (HCC). We demonstrate here that the Hepatitis B viral core protein (HBc) functions as a repressor on the promoter activity of the human p53 gene. The functional analyses of the promoter of the p53 gene by serial deletion, site-directed mutagenesis, and the heterologous promoter system revealed that the promoter activity was repressed through the E2F1-binding site (nucleotides -28 to -8) by HBc. An electrophoretic mobility shift assay (EMSA) showed that the HBc reduced the DNA-binding ability of E2F1 to the binding site of the p53 promoter. The interaction of HBc with E2F1 was also observed by glutathione S-transferase (GST) fusion protein binding assay. Furthermore, HBc represses the expression of the p53 gene in the human liver cell line HepG2. Finally, HBc and HBx synergistically repress both the promoter activity and the expression of the p53 gene in HepG2 cells. These results, together with our previous study, strongly suggest that HBc, like HBx, represses the expression of the human p53 tumor suppressor gene.
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PMID:Transcriptional repression of the human p53 gene by hepatitis B viral core protein (HBc) in human liver cells. 1267 12


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