Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of many viral causes of human cancer, few are of greater global importance than the hepatitis B virus (HBV). Over 250 million people worldwide are persistently infected with HBV. A significant minority of these develop severe pathologic consequences, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Earlier epidemiological evidence suggested a link between chronic HBV infection and HCC. Further, the existence of related animal viruses that induce acute and chronic infections of the liver, and eventually HCC, confirms the concept that HBV belongs to one of the few human oncogenic viruses. Although it is clear that chronic HBV infections are major risk factors, relatively little is understood about how the viral factors contribute to hepatocarcinogenesis. This review will introduce molecular aspects of the viral infection, and highlight recent findings on the viral contribution to hepatocarcinogenesis.
J Biochem Mol Biol 2003 Jan 31
PMID:Molecular aspects of hepatitis B viral infection and the viral carcinogenesis. 1254 84

Interleukin 10 (IL10) is a powerful Th-2 cell cytokine produced by lymphoid cells that exerts its functions by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL1, TNFA, TGFB, IL6, IL8 and IL12). Genetic association analysis of a well-characterized HBV cohort revealed that one of IL10 haplotypes, IL10-ht2, was strongly associated with hepatocellular carcinoma (HCC) occurrence in gene dose-dependent manner. The frequency of susceptible IL10-ht2 was much higher in HCC patients and significantly increased in order of susceptibility to HBV progression from chronic hepatitis to liver cirrhosis and HCC among hepatitis B patients. In addition, survival analysis clearly showed that the onset age of HCC was also accelerated among chronic hepatitis B patients who were carrying IL10-ht2. Increased IL10 production mediated by IL10-ht2 suggests that up-regulated IL10 accelerates progression of chronic HBV infection, especially to HCC development.
Hum Mol Genet 2003 Apr 15
PMID:Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. 1266 13

Macrophage inflammatory protein (MIP-3alpha) is a CC chemokine that attracts immature dendritic cells and lymphocytes and is thought to play a role in the pathogenesis of inflammation and carcinogenesis. However, nothing is known about the clinical significance or prognostic importance of this chemokine in patients with cancer. The aim of this study was to assess the clinical factors influencing the levels of serum MIP-3alpha and to evaluate any possible prognostic importance of this chemokine. We further checked the possible source of MIP-3alpha in hepatocellular carcinoma (HCC). The levels of serum MIP-3alpha from 45 patients with HCC, 12 patients with liver cirrhosis (LC) and 45 patients with chronic hepatitis (CH) were measured by an enzyme immunoassay. A correlationship between different clinical parameters and the serum levels of MIP-3alpha was analyzed. Production of MIP-3alpha by human cancer cell lines and peripheral blood mononuclear cells (PBMC) was also estimated. The levels of serum MIP-3alpha were significantly higher in HCC than in LC (p=0.0214) and CH (p<0.0001). Cancer-related factors such as size of cancer nodules, levels of differentiation of HCC and the levels of alpha-fetoprotein were related with increased MIP-3alpha levels in HCC. Human cancer cell lines, but not PBMC from HCC patients, produced very high levels of MIP-3alpha in culture. The rate of recurrence of HCC after radio frequency ablation (RFA) was fewer in patients having lower pre-therapeutic levels of serum MIP-3alpha. An impact of cancer-related factors on the levels of serum MIP-3alpha in HCC is shown. Pre-therapeutic levels of serum MIP-3alpha may be used as a marker of prognosis of RFA therapy.
Int J Mol Med 2003 May
PMID:Increased serum levels of macrophage inflammatory protein-3alpha in hepatocellular carcinoma: relationship with clinical factors and prognostic importance during therapy. 1268 96

One of the major side effects of ribavirin/interferon alpha combination therapy for chronic hepatitis C is hemolytic anemia. One of the causes of hemolytic anemia is considered to be decreasing deformability of erythrocytes resulting from the accumulation of phosphorylated ribavirin in erythrocytes. The administration of eicosapentaenoic acid (EPA), which has a wide variety of pharmacological actions, increases the deformability of erythrocytes. We conducted an uncontrolled pilot study of EPA therapy for patients with ribavirin-related anemia. Six patients with chronic hepatitis C, who had developed anemia while receiving combination therapy, were treated with an oral ethyl ester of EPA (1800 mg/day) for two months. The hemoglobin level of all six patients increased following EPA therapy. The mean hemoglobin level significantly increased from 10.8 g/dl to 11.4 g/dl one month after therapy was initiated (P<0.05), and this level was obtained again one month later (11.5 g/dl). None of the patients developed an adverse reaction. These findings suggest that EPA has a beneficial effect in patients with ribavirin-related anemia. Further study is required to confirm our results.
Int J Mol Med 2003 Jun
PMID:A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C. 1273 13

Interleukin 6 (IL6) plays an essential role in the regulation of immune response to chronic disease. In this study, the three known single nucleotide polymorphisms (SNPs) in the IL6 promoter region were genotyped in a large chronic hepatitis B cohort to evaluate the effects of IL6 promoter variants. The single base extension method was used for this genotyping. Haplotypes were constructed by the three SNPs in IL6. Allele frequencies were compared for; i) patients with chronic hepatitis (CH) and chronic carriers vs. chronic hepatis patients with clinical evidence of liver cirrhosis (LC) (i.e., portal hypertension), ii) cirrhotic patients with hepatocellular carcinoma (HCC) vs. without HCC by logistic regression, and iii) with respect to the time intervals from the onset of infection to HCC. Results were analyzed by Cox relative hazard analysis on the assumption that all the patients were infected during early infancy. The frequencies of each SNP were 0.002 (IL6-597 G>A), 0.25 (IL6-572 C>G) and 0.002 (IL6-174 G>C), respectively, in the Korean population (n = 1,046). No significant associations were detected between IL6-572 C>G and chronic hepatitis B outcome in this study; i.e., LC occurrence on CH (OR = 0.16-1.27, P = 0.13- 0.71) and HCC occurrence on LC (OR = 1.04-1.23, P = 0.89-0.60) of heterozygotes and homozygotes for G allele in referent comparison to homozygotes for common allele (C/C genotype), and time interval to HCC (RH = 0.67-1.00; P = 0.14-0.99). In conclusion, there appeared to be no significant associations between IL6 promoter variants and disease outcome in chronic hepatitis B.
Exp Mol Med 2003 Apr 30
PMID:Association between interleukin 6 promoter variants and chronic hepatitis B progression. 1275 10

Transforming growth factor-beta1 (TGF-beta1) can act as both a tumor suppressor and a stimulator of tumor progression. We have examined the relationship between polymorphisms of the TGF-beta1 gene and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. A total of 1,237 Korean subjects were prospectively enrolled; 1,046 patients with chronic HBV infection and 191 healthy controls with no evidence of recent or remote HBV infection. The patients were divided into two groups: those without (n = 809) and those with HCC (n = 237). Single nucleotide polymorphisms (SNPs) of TGF-beta1 were searched for and genotyped using the single base extension method. In Korean subjects, only two SNPs were found among the seven known polymorphisms of TGF-beta1, at position -509 and in codon 10. The risk of HCC was significantly lower in patients with the T/T or C/T genotypes than in those with the C/C genotypes at position -509 (P < 0.02), and also lower among those with the Pro/Pro or Leu/Pro genotypes than in those with the Leu/Leu genotypes in codon 10 (P < 0.007). Haplotype analysis revealed that the possession of [-509C > T; L10P] conferred a decreased likelihood of HCC (OR = 0.74; 95% CI, 0.59-0.93; P = 0.008). In conclusion, the presence of the TGF-beta1 -509C > T promoter or of the L10P polymorphism, and the combination of both [-509C > T; L10P] as a haplotype were strongly associated with a reduced risk of HCC in patients with chronic HBV infection.
Exp Mol Med 2003 Jun 30
PMID:Association of transforming growth factor-beta1 gene polymorphisms with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. 1285 19

The recombinant form of the 17kDa, highly hydrophobic and disulfide-bonded hepatitis B virus X protein (HBX) was used for developing a set of monoclonal antibodies (Mab). Our present goal was to determine the fine epitope specificity of our anti-HBX Mab. Based on computer analysis two sequences (amino acids 22-31 and 100-114) were predicted for possessing high immunogenity while the anti-HBX Mab did not recognized them. Limited proteolysis and mass spectroscopic analysis suggested another possible sequence (amino acids 14-26), which also proved to be negative using an immunoserological test. Subsequently, we performed a screen of a phage displayed random peptide library, by which we could localize the epitope to amino acids 88-93. This finding was confirmed using three overlapping fusion peptides spanning amino acids 77-142. Their testing in ELISA assigned the epitope to amino acids 77-95, which supports the result obtained by screening the phage displayed library. Our results suggest the necessity of a complex application of current molecular biological and immunological techniques in fine structure mapping. This approach will be useful to study the prognostic relevance of different antigenic sites on HBX during the development of chronic hepatitis and primary hepatocellular carcinoma.
Mol Immunol 2003 Sep
PMID:Determination of the fine epitope specificity of an anti-hepatitis B virus X protein monoclonal antibody using microanalytical and molecular biological methods. 1294 96

Despite the availability of safe and effective prophylactic vaccines, hepatitis B viral disease has remained a tenacious scourge, ranking ninth globally among all causes of mortality (up to 1 million deaths annually). Approximately 6% of the global population--more than 350 million people--have failed to resolve viral infection and become chronic carriers, eventually placing between 15 and 25% of such individuals at risk for end-stage liver disease. Until recently, the immunomodulator interferon-alpha and especially the nucleoside analog lamivudine (Epivir) have been the treatments of choice for chronic hepatitis B viral infection. However, the inexorable development of drug resistance to lamivudine has been a major clinical impediment to the long-term use of such treatment. Herein, the current and future diagnostic methods for early detection of emerging drug resistance to the hepatitis B virus is reviewed. Given the recent approval of adefovir dipivoxil (Hepsera) and the possibility that other nucleoside and nucleotide analogs could soon become part of the hepatitis B virus therapeutic arsenal, the clinical ramifications for co-ordinated use of diagnostic tests together with new antihepadenaviral agents for optimal patient management is also discussed.
Expert Rev Mol Diagn 2003 Sep
PMID:Early detection of hepatitis B drug resistance: implications for patient management. 1451 Jan 75

Among seven human hepatitis viruses (A to E, G and TT virus), hepatitis B (HBV) and C (HCV) viruses are able to persist in the host for years and principally contribute to the establishment of chronic hepatitis. During the course of persistent infection, continuous intrahepatic inflammation maintains a cycle of liver cell destruction and regeneration that often terminates in hepatocellular carcinoma (HCC). While the expression and retention of viral proteins in hepatocytes may influence the severity and progression of liver disease, the mechanisms of liver injury in viral hepatistis are defined to be due not to the direct cytopathic effects of viruses, but to the host immune response to viral proteins expressed by infected hepatocytes. In the process of liver injury, hepatocellular death (apoptosis) induced by the proapoptotic molecules of T cells activated following antigen recognition triggers a cascade of antigen nonspecific effector systems and causes necroinflammatory disease. Accordingly, the regulation of the immune response, e.g., via the cell death pathways, in chronically infected patients should prevent the development of HCC.
Curr Mol Med 2003 Sep
PMID:Mechanisms of viral hepatitis induced liver injury. 1452 85

The major risk factors and etiological agents responsible for development of hepatocellular carcinoma in humans have been identified and characterized. Among these are chronic infection with hepatitis B virus or hepatitis C virus, exposure to aflatoxin B1, and cirrhosis of any etiology (including alcoholic cirrhosis and cirrhosis associated with genetic liver diseases). Both chronic hepatitis and cirrhosis represent major preneoplastic conditions of the liver as the majority of hepatocellular carcinomas arise in these pathological settings. Hepatocarcinogenesis represents a linear and progressive process in which successively more aberrant monoclonal populations of hepatocytes evolve. Regenerative hepatocytes in focal lesions in the inflamed liver (chronic hepatitis or cirrhosis) give rise to hyperplastic hepatocyte nodules, and these progress to dysplastic nodules, which are thought to be the direct precursor of hepatocellular carcinoma. In most cases, the neoplastic transformation of hepatocytes results from accumulation of genetic damage during the repetitive cellular proliferation that occurs in the injured liver in response to paracrine growth factor and cytokine stimulation. Hepatocellular carcinomas exhibit numerous genetic abnormalities (including chromosomal deletions, rearrangements, aneuploidy, gene amplifications, and mutations), as well as epigenetic alterations (including modulation of DNA methylation). These genetic and epigenetic alterations combine to activate positive mediators of cellular proliferation (including cellular proto-oncogenes and their mitogenic signaling pathways) and inactivate negative mediators of cellular proliferation (including tumor suppressor genes), resulting in cells with autonomous growth potential. However, hepatocellular carcinomas exhibit a high degree of genetic heterogeneity, suggesting that multiple molecular pathways may be involved in the genesis of subsets of hepatocellular neoplasms. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in liver, enabling the development of effective strategies for prevention and/or more effective treatment of hepatocellular carcinoma.
Curr Mol Med 2003 Sep
PMID:Mechanisms of human hepatocarcinogenesis. 1452 88


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