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)

The nonstructural protein 5A (NS5A) of the hepatitis C virus (HCV) has been shown to interact with a variety of cellular proteins and implicated in the regulation of cell growth, interferon resistance, and other cellular signaling pathways, but the role of NS5A in HCV pathogenesis has not been firmly established. To further characterize this multifunctional protein, we instigated the studies of the subcellular localization of NS5A in a hepatoma cell line. NS5A was localized to the perinuclear membrane structures, including the endoplasmic reticulum (ER) and the Golgi apparatus, by immunofluorescence staining and confocal microscopy. In addition, it was also associated with the surface of cytoplasmic globular structures when expressed alone or as a part of the NS3-5B polyprotein. Oil red O staining revealed that these globular structures were lipid droplets, where the HCV core protein was also localized. The association of NS5A with intracellular membrane was further confirmed by membrane flotation analysis. To determine whether NS5A interacts with any cellular lipid-binding protein, we performed yeast two-hybrid screening in both HepG2 and human liver cDNA libraries. Apolipoprotein A1 (apoA1), one of the protein components of high-density lipoprotein (HDL) particles, was identified by two independent screening processes. The interaction between NS5A and apoA1 was confirmed by both in vitro pull-down and in vivo coimmunoprecipitation experiments. Immunofluorescence staining revealed a significant colocalization of NS5A and apoA1 in the Golgi apparatus. Our results established an association of NS5A with lipid droplets and apoA1, suggesting that NS5A, together with the core protein, may play a role in the pathogenesis of the derangement of lipid metabolism, contributing to liver steatosis commonly observed in hepatitis C.
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PMID:Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. 1187 23

The recently developed subgenomic hepatitis C virus (HCV) replicons were limited by the fact that the sequence encoding the structural proteins was missing. Therefore, important information about a possible influence of these proteins on replication and pathogenesis and about the mechanism of virus formation could not be obtained. Taking advantage of three cell culture-adaptive mutations that enhance RNA replication synergistically, we generated selectable full-length HCV genomes that amplify to high levels in the human hepatoma cell line Huh-7 and can be stably propagated for more than 6 months. The structural proteins are efficiently expressed, with the viral glycoproteins E1 and E2 forming heterodimers which are stable under nondenaturing conditions. No disulfide-linked glycoprotein aggregates were observed, suggesting that the envelope proteins fold productively. Electron microscopy studies indicate that cell lines harboring these full-length HCV RNAs contain lipid droplets. The majority of the core protein was found on the surfaces of these structures, whereas the glycoproteins appear to localize to the endoplasmic reticulum and cis-Golgi compartments. In agreement with this distribution, no endoglycosidase H-resistant forms of these proteins were detectable. In a search for the production of viral particles, we noticed that these cells release substantial amounts of nuclease-resistant HCV RNA-containing structures with a buoyant density of 1.04 to 1.1 g/ml in iodixanol gradients. The same observation was made in transient-replication assays using an authentic highly adapted full-length HCV genome that lacks heterologous sequences. However, the fact that comparable amounts of such RNA-containing structures were found in the supernatant of cells carrying subgenomic replicons demonstrates a nonspecific release independent of the presence of the structural proteins. These results suggest that Huh-7 cells lack host cell factors that are important for virus particle assembly and/or release.
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PMID:Persistent and transient replication of full-length hepatitis C virus genomes in cell culture. 1190 40

Hepatic steatosis and hepatocellular carcinoma (HCC) are common and serious features of hepatitis C virus (HCV) infection, and the core protein has been shown to play distinct roles in the pathogenesis. Here we report the direct interaction of HCV core protein with retinoid X receptor alpha (RXRalpha), a transcriptional regulator that controls many aspects of cell proliferation, differentiation, and lipid metabolism. The core protein binds to the DNA-binding domain of RXRalpha, leading to increase the DNA binding of RXRalpha to its responsive element. In addition, RXRalpha is activated in cells expressing the core protein as well as in the livers of the core-transgenic mice that would develop hepatic steatosis and HCC later in their lives. Using promoter genes of cellular retinol binding protein II (CRBPII) and acyl-CoA oxidase as reporters, we also show that the expression of the core protein enhances the transcriptional activity regulated by the RXRalpha homodimer as well as by the heterodimer with peroxisome proliferator activated receptor alpha. Furthermore, expression of the CRBPII gene is also up-regulated in the livers of HCV core-transgenic mice. In conclusion, these results suggest that modulation of RXRalpha-controlled gene expression via interaction with the core protein contributes to the pathogenesis of HCV infection.
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PMID:Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. 1191 42

Data suggesting that the hepatitis C virus (HCV) core protein influences normal cellular processes remain controversial. To determine the effects of core on cellular gene expression in hepatocytes, we developed a human hepatoma (Huh7)-derived cell line with tightly regulated core expression under the control of a tetracycline-regulated promoter. Cells expressing core did not have impaired proliferative abilities. Changes in gene expression profiles in response to core expression were determined using commercial oligonucleotide microarrays (Affymetrix GeneChip). Significant increases were observed in the abundance of mRNA-encoding members of the metallothionein (MT) family, as well as nicotinamide N-methyltransferase (NNMT) and glutathione peroxidase-like protein (GPLP). These changes did not result from removal of tetracycline from growth media, and were confirmed in reverse-transcription polymerase chain reaction (RT-PCR) assays. They suggest that core protein expression leads to intracellular oxidative stress, and that vital cellular functions are, in turn, protected by up-regulation of cellular antioxidant defense mechanisms. In conclusion, these findings can explain many potentially conflicting prior observations concerning the effects of core on cellular physiology, and are of relevance to the role of core protein in the pathogenesis of HCV-related fibrosis and hepatocellular carcinoma.
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PMID:Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells. 1198 74

Overwhelming lines of epidemiologic evidence have indicated that chronic infection with hepatitis C virus (HCV) poses a major risk towards the development of hepatocellular carcinoma (HCC). It remains controversial whether HCV plays a direct role in the pathogenesis of HCV-associated HCC or whether it merely serves an indirect role. Using the transgenic mouse model established by us, it has become evident that the core protein of HCV confers oncogenic potential. The findings in our studies indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors, such as continued cell death and regeneration associated with chronic hepatitis, may also play a role. Taken together, our results indicate that there could be a mechanism for the development of HCC in persistent hepatitis virus infection that is distinct from the pathogenesis of other cancers, like colorectal cancer. Thus, although accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC, HCV core protein, to which an oncogenic potential is ascribed, may allow some stages to be skipped in hepatocarcinogenesis. The possibility that infection with HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations would help explain the unusually high incidence and multicentric nature of HCC developing in chronic hepatitis C.
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PMID:Role of hepatitis C virus in the development of hepatocellular carcinoma: transgenic approach to viral hepatocarcinogenesis. 1198 18

Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is common and is associated with a more severe liver disease and increased frequency in the development of hepatocellular carcinoma (HCC). Here, we demonstrated that HBV X protein (HBx) and HCV core protein additively repress the universal cyclin-dependent kinase inhibitor p21 gene at the transcription level. The transforming growth factor-beta responsive element and Sp1 site of the p21 promoter were responsible for the effect of HCV core and HBx, respectively. Furthermore, cell growth was additively stimulated by them, suggesting that additive repression of the p21 might be important to understand the cooperative development of HCC by HBV and HCV.
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PMID:Cooperative repression of cyclin-dependent kinase inhibitor p21 gene expression by hepatitis B virus X protein and hepatitis C virus core protein. 1199 40

Hepatitis C virus (HCV) chronic infection has been associated with many lymphoproliferative disorders. Several studies performed on hepatoma and fibroblast cell lines suggest a role of the HCV core protein in activation of cellular transduction pathways that lead to cell proliferation and inhibition of apoptosis. However, no data are available concerning the effects of HCV core expression on B-lymphocyte proliferation and apoptosis. B-lymphocyte cell lines permanently expressing full-length HCV 1b core sequences isolated from chronically infected patients were established using B-cell lines at different degrees of differentiation. Clones and pools of clones permanently expressing the HCV core were selected and characterized for protein expression by Western blot and FACS. Expression of HCV core proteins did not significantly enhance cell proliferation rates under normal culture conditions or under mitogenic stimulation. Analysis of NF-kappa B, CRE, TRE and SRE pathways by luciferase reporter genes did not show a significant influence of HCV core expression on these signal transduction cascades in B-lymphocytes. The effects of HCV core on anti-IgM and anti-FAS-induced apoptosis in B-cell lines was also analysed. In this experimental model, HCV core expression did not significantly modify the apoptotic profile of the B-lymphocyte cell lines tested. These data underline a cell type-specific effect of HCV core expression. In fact, it was not possible to show a significant contribution of the HCV core protein in activation of the major B-cell signal transduction pathways involved in the regulation of proliferation and programmed cell death, which is in contrast with the results reported in hepatoma cell lines.
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PMID:Hepatitis C virus core protein expression in human B-cell lines does not significantly modify main proliferative and apoptosis pathways. 1207 85

We have shown that highly proofreading DNA polymerase is required for the polymerase chain reaction in the genetic analysis of hepatitis C virus (HCV). To clarify the status of HCV quasispecies in hepatic tissue using proofreading DNA polymerase, we performed a genetic analysis of the HCV core protein-encoding region in cancerous and noncancerous lesions derived from 4 patients with hepatocellular carcinoma. In contrast to the previously published data, we observed neither deletions nor stop codons in the analyzed region and no significant difference in the complexity of HCV quasispecies between cancerous and noncancerous lesions. This result suggests that the HCV core gene is never structurally defective in hepatic tissues, including cancerous lesions. However, in 3 of the patients, the consensus HCV species differed between cancerous and noncancerous lesions, suggesting that the predominant replicating HCV species differs between these 2 types of lesions. Moreover, during the course of the study, we obtained several interesting variants possessing a substitution at codon 9 of the core gene, whose substitution has been shown to induce the production of the F protein synthesized by a - 2/+1 ribosomal frameshift.
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PMID:Hepatitis C virus quasispecies in cancerous and noncancerous hepatic lesions: the core protein-encoding region. 1210 85

Hepatitis C virus (HCV) causes chronic hepatitis and is linked to the development of hepatocellular carcinoma (HCC). The role of HCV infection in the development of HCC remains to be clarified. We analyzed the effect of HCV core protein on modulation of cell proliferation. HCV core protein was shown to have at least two functions: activation of the Ras/Raf signaling pathway and anti-apototic function.
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PMID:Hepatitis C virus and its roles in cell proliferation. 1210 66

Over the past decade, genetically engineered mouse models have been used for studies of the mechanisms underlying human diseases. One advantage of these models is that the targeted protein executes its function in normal cells in their natural tissue microenvironments. Transgenic mouse models for human viral hepatitis have also been established and have provided new insights into the pathogenesis of hepatitis and hepatocellular carcinoma (HCC). In the search for the mechanism of hepatocarcinogenesis in hepatitis viral infection, two viral proteins, the core protein of hepatitis C virus (HCV) and the HBx protein of hepatitis B virus (HBV), have been shown to possess oncogenic potential through transgenic mouse studies, indicating the direct involvement of the hepatitis viruses in hepatocarcinogenesis. The presence of the hepatitis C virus core or HBx protein, which has an oncogenic potential, may allow some of the steps in multistep hepatocarcinogenesis to be skipped. This may explain the very high frequency of HCC in patients with HCV or HBV infection.
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PMID:Hepatocarcinogenesis in hepatitis viral infection: lessons from transgenic mouse studies. 1210 67


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