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)

Chronic infection with hepatitis C virus (HCV) may lead to liver failure and hepatocellular carcinoma. Current treatment for HCV includes high systemic doses of interferonalpha (IFNalpha), which is effective in less than half of patients and may have severe side effects. We designed conditional IFNalpha and IFNgamma expression constructs to be triggered by HCV-induced activation of NFkappaB, and delivered these using highly efficient recombinant Tag-deleted SV40-derived vectors. NFkappaB activates the HIV-1NL4-3 long terminal repeat (HIVLTR) as a promoter, which accounts for the conditional transgene expression. Human hepatocyte lines and primary rat hepatocytes (PRH) were transduced with SV[HIVLTR](IFN) vectors, and transfected with HCV cDNA. Production of human and murine IFNalpha and IFNgamma in cytosol and culture supernatants was measured. HCV activated the HIVLTR to produce and secrete IFNs, and did so largely through the NFkappaB binding sites of the HIVLTR. Levels of IFNs secreted, and the magnitude of induction in response to HCV, were greater in hepatocyte lines than in primary cultured hepatocytes. However, even in the latter, supernatant IFNalpha concentrations achieved by this approach were similar to therapeutic serum concentrations sought in systemic IFNalpha-treated patients. In coculture studies, secreted IFNalpha activated its cognate response elements in untransduced cells, suggesting that its potential inhibitory effects on HCV may not be limited to transduced cells. Although HCV replication in culture is difficult to assess, HCV-induced IFNalpha production demonstrably reduced HCV transcription. Conditional expression of IFNs within the liver may represent an attractive approach to therapy of severe chronic HCV infection that could avoid the side effects of systemic treatment regimens.
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PMID:Exploiting hepatitis C virus activation of NFkappaB to deliver HCV-responsive expression of interferons alpha and gamma. 1450 15

Chronic infection with hepatitis B virus (HBV) causes DNA damage. An arginine (Arg)-to-glutamine (Gln) polymorphism at codon 399 in the XRCC1 gene is putatively associated with DNA damage. In a case-control study of 577 HBV surface antigen carriers with hepatocellular carcinoma (HCC) and 389 HBV carrier control subjects, we investigated the association between this polymorphism and the risk of HCC and assessed whether this association varied with glutathione S-transferase (GST) status; GSTs are involved in carcinogen metabolism. All statistical tests were two-sided. The XRCC1 Gln allele was associated with a dose-dependent increased risk of early-onset HCC (<50 years) but not with the risk of late-onset HCC (P(trend) =.01). The GSTT1-null genotype alone did not affect risk, but the GSTM1-null genotype was associated with a decreased risk for early-onset HCC. Various combinations of GSTM1 and GSTT1 genotypes differentially modified the association of XRCC1 with HCC (P(interaction) =.005); e.g., for individuals with the GSTT1-null/GSTM1-present genotype, the risk of HCC was greater for those with the Gln/Gln genotype (odds ratio = 8.07, 95% confidence interval = 1.67 to 38.93) than for those with the Arg/Arg genotype. Thus, GST status appears to affect the risk of HCC associated with this XRCC1 polymorphism.
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PMID:Polymorphisms in XRCC1 and glutathione S-transferase genes and hepatitis B-related hepatocellular carcinoma. 1451 56

1. Chronic infection with hepatitis C virus (HCV) is the leading cause of cirrhosis and the most common indication for liver transplantation in many countries throughout the world. 2. The most significant factors leading to fibrosis progression in patients with chronic HCV infection include the degree of inflammation present on liver biopsy and ongoing alcohol use. 3. Patients with cirrhosis secondary to chronic HCV infection are at increased risk for developing hepatocellular carcinoma (HCC). 4. Achieving a sustained virological response after treatment with interferon, with or without ribavirin, is associated with a reduced risk for the development of cirrhosis and HCC and prolonged survival.
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PMID:Natural history and risk factors for progression of hepatitis C virus disease and development of hepatocellular cancer before liver transplantation. 1458 90

Chronic infection with hepatitis B virus (HBV) has been reported in two-thirds of cases of hepatocellular carcinoma (HCC) in Greece from 1973 to 1995, while chronic hepatitis C virus (HCV) infection in 10% of them. We studied the roles of HBV and HCV in HCC in Greece between 1996 and 2000 compared with the past, and possible differences in clinical and laboratory characteristics of HBV- and HCV-related HCC. Complete clinical and laboratory data from 306 patients with HCC, diagnosed from January 1996 to December 2000, were analyzed. Chronic HBV and HCV infection were detected in 52.3 and 21.6% of the patients, respectively. The ratio of HBV- to HCV-related HCC was 2.42. Compared with the data prior to 1996, there was a 101.8% increase in the relative frequency of HCV (P < 0.0001) and an 11.8% decrease in that of HBV (P = 0.033), with a -56.3% change in the ratio of HBV- to HCV-related HCC cases. Statistically significant differences in the male/female ratio, median age and frequency of multifocal lesions were found in HBV- vs HCV-related HCC. Although HBV still represents the major aetiological factor of HCC in Greece, its role has significantly decreased in the last 5 years, while a more significant increase has occurred in HCV-related HCC. The two aetiological types of HCC differ in Greece in demographic, epidemiological and other features.
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PMID:Changing relative roles of hepatitis B and C viruses in the aetiology of hepatocellular carcinoma in Greece. Epidemiological and clinical observations. 1463 79

Hepatocellular carcinoma (HCC) is one of the 10 most common malignant tumors worldwide. Chronic infection with hepatitis B or C virus is closely related to hepatocarcinogenesis. The outcome of current therapies for HCC is not satisfactory. Prevention is the best way to control HCC. Among the various strategies of HCC prevention, immunization against hepatitis B virus infection is the most effective. Universal hepatitis B immunization has proved to be effective in reducing the incidence of HCC to 1/4-1/3 of that in children born before the hepatitis B vaccination era in Taiwan. The problems we face in achieving global control of hepatitis-related HCC include: (1) no effective vaccine for the prevention of hepatitis C and its related HCC; (2) no immunization program for hepatitis B in areas with inadequate resources; (3) poor compliance to the immunization program as a result of ignorance, anxiety, or poverty; and (4) vaccine failure. Integration of the hepatitis B vaccination program into the expanded program of immunization for all infants throughout the world will be most urgent and important for HCC control. The reduction of the incidence of HCC will be seen in adults 30-40 years of age after the launch of the universal hepatitis B vaccination program. This concept of cancer vaccine can be applied to other infectious agents and their related cancers.
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PMID:Decreasing incidence of hepatocellular carcinoma among children following universal hepatitis B immunization. 1470 90

Chronic infection with hepatitis C virus is very frequent among hemophilic patients in all developed counties, including the Czech Republic. Because of a possibility of developing serious terminal stages of infection, liver cirrhosis and hepatocellular carcinoma, the tendency in treatment of patients with chronic hepatitis C is to start it as soon as possible and thus reduce the probability of developing these advanced stages of disease which are difficult to treat. Treatment of hemophilic patients with chronic hepatitis C started in the Department of Infectious Diseases, University Hospital Brno Bohunice, in 1996. Used treatment schemes have reflected historical evolution of treatments used to treat chronic hepatitis C. Initially, alpha-interferon (IFN) was administered in monotheraphy (6 patients), later, since 1999, a combination of alpha-IFN and ribavirin was administered (13 patients), and since 2001 a combination of pegylated interferon (PEG-IFN) and ribavirin (3 patients) was administered. In all the patients the individual treatments took 12 month. Sustained negativization of HCV RNA in serum has not been achieved in any patient treated only with alpha-IFN. In patients who were administered the combination of alpha-IFN and ribavirin this effect appeared in 4 from 7 cases without history of treatment with alpha-IFN (57%), one from 2 relapses and one from 3 non-responders. The combination PEG-IFN and ribavirin was effective in the only one patient who relapsed after alpha-IFN and ribavirin and in one from the two non-responders to this combination. The tolerance and safety of treatment was good in haemophilia patients and could be fully compared to those in other patients with chronic hepatitis C.
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PMID:[Successful treatment of chronic hepatitis C in hemophiliacs based on historical development of therapeutic protocols]. 1501 27

Hepatitis C virus (HCV) infects over 170 million people worldwide. Chronic infection occurs in 50-80% of cases and eventually leads to cirrhosis and hepatocellular carcinoma. The HCV lifecycle is only partly understood owing to the lack of a productive cell culture system. Several molecules have been implicated in the receptor complex at the surface of target cells, but the mode of HCV entry remains unknown. Persistent infection appears to be due to weak CD4+and CD8+ T-cell responses during acute infection, which fail to control viral replication. When chronic infection is established, HCV does not appear to be cytopathic. Liver lesions appear to result from locally driven immune responses, which are mainly non-specific. Local inflammation triggers fibrogenesis, in which hepatic stellate cells play a major role. Cirrhosis is facilitated by external factors, such as chronic alcohol consumption and viral co-infections. Patients with cirrhosis are at high risk of developing hepatocellular carcinoma. The role of HCV proteins in hepatocarcinogenesis is unknown. Further progress in our understanding of HCV infection and pathogenesis awaits the advent of new model systems and technologies.
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PMID:Pathophysiology of hepatitis C virus infection and related liver disease. 1503 26

Chronic infection by hepatitis C virus (HCV) can lead to severe hepatitis and cirrhosis and is closely associated with hepatocellular carcinoma. The replication cycle of HCV is poorly understood but is likely to involve interaction with host factors. In this report, we show that NS5B, the HCV RNA-dependent RNA polymerase (RdRp), interacts with a human RNA helicase, p68. Transient expression of NS5B alone, as well as the stable expression of all the nonstructural proteins in a HCV replicon-bearing cell line (V. Lohmann, F. Korner, J.-O. Koch, U. Herian, L. Theilmann, and R. Bartenschlager, Science 285:110-113), causes the redistribution of endogenous p68 from the nucleus to the cytoplasm. Deletion of the C-terminal two-thirds of NS5B (NS5BDeltaC) dramatically reduces its coimmunoprecipitation (co-IP) with endogenous p68, while the deletion of the N-terminal region (NS5BDeltaN1 and NS5BDeltaN2) does not affect its interaction with p68. In consistency with the co-IP results, NS5BDeltaC does not cause the relocalization of p68 whereas NS5BDeltaN1 does. With a replicon cell line, we were not able to detect a change in positive- and negative-strand synthesis when p68 levels were reduced using small interfering RNA (siRNA). In cells transiently transfected with a full-length HCV construct, however, the depletion (using specific p68 siRNA) of endogenous p68 correlated with a reduction in the transcription of negative-strand from positive-strand HCV RNA. Overexpression of NS5B and NS5BDeltaN1, but not that of NS5BDeltaC, causes a reduction in the negative-strand synthesis, indicating that overexpressed NS5B and NS5BDeltaN1 sequesters p68 from the replication complexes (thus reducing their replication activity levels). Identification of p68 as a cellular factor involved in HCV replication, at least for cells transiently transfected with a HCV expression construct, is a step towards understanding HCV replication.
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PMID:Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. 1511 10

Chronic infection by HCV is closely correlated with liver diseases such as cirrhosis, steatosis, and hepatocellular carcinoma. To understand how long-term interaction between HCV and the host leads to pathogenesis, we identified cellular proteins that interact with NS5A and NS5B using a biochemical approach. Stable cell lines that express flag-NS5A or flag-NS5B under tetracycline induction were generated. The induced flag-tagged proteins were immunoprecipitated (IP'd) and associated proteins separated on 2D gels. Protein spots that specifically co-IP'd with NS5A or NS5B were identified by mass spectrometry. HSP27 was identified as a protein that specifically co-IP'd with NS5A but not with NS5B. The N-terminal regions of NS5A (a.a. 1-181) and HSP27 (a.a. 1-122) were defined to be the domains that interact with each other. HSP27 is generally distributed in the cytoplasm. When heat shocked, HSP27 is concentrated in the ER where NS5A is co-localized.
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PMID:Proteomic approach identifies HSP27 as an interacting partner of the hepatitis C virus NS5A protein. 1512 Jun 31

Chronic infection with hepatitis B virus (HBV) is an important clinical problem due to its worldwide distribution and potential of adverse sequelae including hepatocellular carcinoma (HCC). Hepatitis B e antigen (HBeAg) is a biomarker of active viral proliferation in hepatocytes and infectivity. The prevalence of HBeAg among subjects chronically infected with HBV decreases with the increase in age. Case series studies have found a lowest seroprevalence of HBeAg in HCC patients compared with patients affected with chronic hepatitis B and liver cirrhosis. Case-control studies have shown a significantly higher seroprevalence of HBeAg in HCC cases than matched controls. A recent long-term follow-up study has shown a significantly elevated HCC risk for seropositives of both hepatitis B surface antigen (HBsAg) and HBeAg compared with seropositives of HBsAg only and seronegatives. The biological gradient remained in further stratification analyses by serum level of alanine transaminase and status of liver cirrhosis detected by ultrasonography. The cumulative HCC risk from age 30 to 70 years has been estimated to be 87% for those who were persistently seropositive on HBsAg and HBeAg, 12% for those with persistent seropositivity of HBsAg only, and 1% for those who were seronegative on HBsAg and HBeAg.
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PMID:Seropositivity of hepatitis B e antigen and hepatocellular carcinoma. 1518 77


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