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 B virus (HBV) is a major risk factor for hepatocellular carcinoma. The HBV X protein (HBx) is thought to have oncogenic potential, although the molecular mechanism remains obscure. Pathological roles of HBx in the carcinogenic process have been examined using rodent systems and no report is available on the oncogenic roles of HBx in human cells in vitro. We therefore examined the effect of HBx on immortalization and transformation in human primary cells. We found that HBx could overcome active RAS-induced senescence in human immortalized cells and that these cells could form colonies in soft agar and tumors in nude mice. HBx alone, however, could contribute to neither immortalization nor transformation of these cells. In a population doubling analysis, an N-terminal truncated mutant of HBx, HBx-D1 (amino acids 51-154), which harbors the coactivation domain, could overcome active RAS-induced cellular senescence, but these cells failed to exhibit colonigenic and tumorigenic abilities, probably due to the low expression level of the protein. By scanning a HBx expression library of the clustered-alanine substitution mutants, the N-terminal domain was found to be critical for overcoming active RAS-induced senescence by stabilizing full-length HBx. These results strongly suggest that HBx can contribute to carcinogenesis by overcoming active oncogene-induced senescence.
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PMID:Hepatitis B virus X protein overcomes oncogenic RAS-induced senescence in human immortalized cells. 1776 Sep 51

Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause persistent viral infection in humans. Chronic infection is associated with a risk of cirrhosis and hepatocellular carcinoma. The cause of chronic infection is unknown. A large body of evidence suggests that a failure of the adaptive immune response is critical in the establishment of chronic infection. Recently a new group of T cells (T-regulatory cells), that express CD4(+)CD25(+) and Foxp3, which can inhibit the cellular (CD4(+)/CD8(+)) immune response have been described. In this review the authors explore the thoughts regarding immune responses to HBV and HCV infections and the role of these T-regulatory cells in relation to the pathogenesis of chronic HBV and HCV infection and the potential for therapeutic intervention.
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PMID:T-regulatory lymphocytes and chronic viral hepatitis. 1796 Oct 92

Hepatitis B virus (HBV) is a small DNA virus that targets the liver almost exclusively. Chronic infection with HBV might lead to severe liver-related pathologies including chronic hepatitis, cirrhosis and hepatocellular carcinoma. Based on its enhancer composition, which links nutritional signals that control hepatic glucose and fat metabolism in the liver to HBV gene expression and replication, it appears that the virus has adopted a regulatory system that is unique to the major hepatic metabolic genes. This unique virus-host interaction, mediated by metabolic events in the liver, is designated by us the "metabolovirus model". We hypothesize that by mimicking the expression of key genes implicated in glucose homeostasis, HBV sophisticatedly exploits the host resources to ensure its persistence. Specifically, by recruiting transcription factors and coactivators common to essential hepatic metabolic genes the virus avoids a possible resistance by its host, on the one hand, and ensures a timely and proper response to changes in its environment in terms of metabolic milieu, on the other hand. Furthermore, by coupling its gene expression to the expression of hepatic metabolic genes that fluctuate during the day, we predict a fluctuating nature of HBV gene expression. This can serve the virus in its attempts to escape the host immune system in addition to other immune evading strategies adopted by the virus, such as the secretion of the e antigen. Based on our "metabolovirus model", we suggest new mechanisms to previously unexplained clinical phenomena, such as the observed diversity in disease severity between different geographical areas that differ in nutritional habits. Furthermore, given the up-regulatory effect of food deprivation on HBV gene expression and replication, we suggest that conditions of short-term starvation should be completely avoided by HBV-infected individuals, and dietary recommendations such as the ingestion of complex carbohydrates before sleep should be adopted. Thus, our hypothesis sets the stage for viral manipulation by controlling food intake, and opens additional avenues towards food or nutritional therapy as an effective anti-HBV weapon.
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PMID:The "metabolovirus" model of hepatitis B virus suggests nutritional therapy as an effective anti-viral weapon. 1833 85

Chronic infection with hepatitis B affects nearly 350 million individuals worldwide and is the leading cause of hepatocellular carcinoma and liver cirrhosis. Universal infant immunization has decreased rates of HBV infection, although transmission continues to occur via vertical (mother-to-child) and horizontal (sexual, parenteral and household) routes. Treatments are now available for children with chronic HBV infection, but appropriate selection of those most likely to respond to treatment is important. Interferon alpha and lamivudine are currently approved in the US for the treatment of children older than 2 years of age who have chronic HBV infection. Hepatitis C infection affects almost 170 million individuals worldwide. Of individuals exposed to HCV, 60-80% develop chronic hepatitis, and 10-15% of those chronically infected develop cirrhosis within several decades. No vaccine exists for HCV; therefore, prevention of parenteral transmission is important. A high index of suspicion is essential for the diagnosis of HCV infection given its silent clinical presentation. Appropriate evaluation of infected individuals is warranted when considering their suitability for therapy. Interferon alpha and ribavirin, used in combination, are currently approved in the US for the treatment of children older than 3 years of age with chronic HCV infection.
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PMID:Hepatitis B and C in children. 1841 57

Chronic infection of hepatitis B virus (HBV) is one of the major causes of hepatocellular carcinoma (HCC) in the world. The hepatitis B virus X protein (HBx) is implicated in HCC development, although its oncogenic role remains controversial. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progress, and DNA repair by directly or indirectly interacting with host factors. We constructed the HBx stably expressing HepG2 cell line to investigate the impact of HBx on intra-S-phase checkpoint induced by mitomycin C (MMC). The HBx transformed HepG2 cells are more sensitive to MMC treatment and showed defective radioresistant DNA synthesis compared to the control cell line transformed with empty vector. With DNA content assay, HBx transformed cells showed defective S phase arrest and a consequent G2/M arrest after MMC treatment. HBx impaired the ATR dependent phosphorylation of Chk1 and monoubiquitination of FANCD2. Overexpression of ATR reverted the MMC induced phenotype of Chk1 and FANCD2 in HBx transformed cells. The defect of intra-S-phase checkpoint resulted in accumulation of genomic instability. In conclusion, HBx disrupts intra-S-phase checkpoint induced by MMC through ATR-Chk1 and ATR-FANCD2 pathways.
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PMID:Hepatitis B virus X protein disrupts DNA interstrand crosslinking agent mitomycin C induced ATR dependent intra-S-phase checkpoint. 1849 7

Chronic infection with hepatitis B virus can lead to liver disease, cirrhosis, and hepatocellular carcinoma. Treatment options include interferons and antiviral drugs. The interferons have immunomodulatory, antiproliferative, and antiviral effects. Nucleoside analogs, such as entecavir, lamivudine and telbivudine, and neucleotide analogs, such as adefovir and tenofovir, exhibit antiviral effects by inhibiting viral replication. Treatment is directed at suppressing viral replication and halting the progression of disease.
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PMID:Pharmacotherapy of hepatitis B infection: a brief review. 1885 82

Currently, >350 million people worldwide are affected by chronic infection with the hepatitis B virus (HBV). Chronic infection may cause cirrhosis and hepatocellular carcinoma; HBV infection is responsible for 328,000 cancer deaths per year. In areas of high HBV endemicity, most infections occur early in life; infected children do not mount an effective immune response and exhibit immune tolerance, so that the risk of chronic infection is high. In areas of low endemicity, infections tend to be in adults within defined risk groups, and the risk of chronicity is much lower. Population migration from areas of high endemicity to areas of low endemicity is creating pockets of HBV infection in areas of low general prevalence, necessitating improved efforts to screen, vaccinate, and treat. Chronic HBV infection is a complicated, nonlinear disease with a variable course of progression; predictors of progression include the duration of time in the immunoactive phase of disease that follows the immune tolerant phase when hepatocytes are attacked. Additionally, the duration of a high viremic state, with ongoing clinical hepatitis and possibly concurrent infections (e.g., hepatitis C, human immunodeficiency virus), influence outcome. Targeted vaccination of high-risk groups has many limitations. Universal childhood vaccination to prevent chronic infection and its sequelae is the only approach that will lead to the global elimination of chronic HBV infection.
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PMID:Demography and presentation of chronic hepatitis B virus infection. 1918 72

Chronic infection with the hepatitis B virus (HBV) is the most important risk factor for hepatocellular carcinoma (HCC). However, determinants of HCC risk in infected individuals are not well understood. We prospectively evaluated the association between acquired HBV 1762(T)/1764(A) double mutations and HCC risk among 49 incident HCC cases and 97 controls with seropositive hepatitis B surface antigen at baseline from a cohort of 18,244 men in Shanghai, China, enrolled during 1986 to 1989. Compared with HBV carriers without the mutations, chronic HBV carriers with the HBV 1762(T)/1764(A) double mutations experienced an elevated risk of HCC (odds ratio, 2.47; 95% confidence interval, 1.04-5.85; P = 0.04). Risk increased with increasing copies of the double mutations; men with > or =500 copies/microL serum had an odds ratio of 14.57 (95% confidence interval, 2.41-87.98) relative to those without the double mutations (P(trend) = 0.004). Thus, the HBV 1762(T)/1764(A) double mutation is a codeterminant of HCC risk for people chronically infected with HBV.
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PMID:Prospective evaluation of hepatitis B 1762(T)/1764(A) mutations on hepatocellular carcinoma development in Shanghai, China. 1919 Jan 66

Chronic infection with the hepatitis B virus has been linked epidemiologically to the development of hepatocellular carcinoma for more than 30 years. Although the mechanisms by which chronic hepatitis B viral infection results in hepatocellular carcinoma are unclear, there is good evidence that the virus itself exerts a direct hepatocarcinogenic effect, and this has implications for prevention. First, programs of universal infant vaccination have been shown to be effective in reducing the rate of hepatocellular carcinoma among children. This benefit should be translated into adulthood among vaccine recipients. Second, it has been suggested that antiviral therapy against hepatitis B may reduce the risk of hepatocellular carcinoma. Antiviral therapy against hepatitis B is effective in causing prolonged lowering of serum levels of hepatitis B virus DNA. There are emerging data showing that prolonged antiviral therapy may reduce the risk of hepatocellular carcinoma among certain patients with chronic hepatitis B.
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PMID:Hepatitis B and hepatocellular carcinoma. 1939 7

Chronic infection with hepatitis C virus (HCV) is regarded as a risk factor for hepatocellular carcinoma (HCC), mostly in patients with liver cirrhosis. Present study aimed at evaluation of cellular expression of p53 protein, genetic TP53 changes in liver samples and anti-p53 in serum of patients with chronic hepatitis C virus infection. The expression of p53 protein were analysed by immunocytochemistry in liver biopsies from adult patients with chronic, long-lasting hepatitis C. In order to detect TP53 mutations, PCR/SSCP and sequencing were performed. Antibodies against p53 in serum were determined using enzyme immunoassay (ELISA).In two out of 14 examined patients TP53 point mutations were detected in the liver samples. In the first patient, a substitution of C to T was demonstrated in position 1 of the codon 250, resulting in substitution of proline by serine. The other patient carried a substitution of C to G in position 13274 of the intron 6. The patient carrying mutation in the codon 250 demonstrated morphological traits of liver cirrhosis and had high number of p53-immunoreactive cell nuclei in tissue. None of the patients manifested elevated titres of serum anti-p53. In the liver, significant positive correlations were disclosed between expression of p53 on one hand and grading and staging on the other. A negative correlation was disclosed between cellular expression of p53 and duration time of infection. In conclusions, genetic changes in TP53 can be detected also in non-neoplastic lesions linked to chronic HCV infection.
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PMID:p53 immunocytochemistry and TP53 gene mutations in patients with chronic hepatitis C virus (HCV) infection. 1941 35


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