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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic hepatitis B progresses across a spectrum of asymptomatic carriers, active hepatitis, and liver cirrhosis. With more advanced disease stage, the risk for developing hepatocellular carcinoma (HCC) becomes higher. Recent studies suggest that this progressive risk may reflect an accumulation of multistage genetic mutations in the chromosomes of affected hepatocytes. Mutations of the known candidate genes such as p53 and beta-catenin have been found. Recent genome-wide analysis of HCC chromosomes by comparative genomic hybridization or loss of heterozygosity have identified more new loci implicated in hepatocarcinogenesis. Persistent hepatitis B is essential for inducing these mutations through immune-mediated injuries of the hepatocytes and the resulting hyperplasia. Prevention of hepatitis B by active immunization effectively interrupts persistent viral infections in children and subsequently reduces the risk of childhood HCC. Treatment for chronic hepatitis B by interferon or antiviral analogues can control hepatitis B activity, but its effect on controlling HCC remains to be seen. Insights for the hepatocarcinogenesis process should come from a multidisciplinary collaboration to explore important viral and host genes so that new approaches to diagnosis and treatment can be developed.
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PMID:Hepatitis B virus infection and hepatocellular carcinoma: molecular genetics and clinical perspectives. 1051 5

The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of beta-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of beta-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Delta mice harbored either a deletion of the wt p53 allele or a beta-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene. Oncogene (2000).
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PMID:Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles. 1085 Oct 67

To better understand the role of beta-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. beta-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had beta-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3beta region of beta-catenin. Outside the GSK-3beta phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P: < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P: < 0.00001), and higher male-to-female ratio (P: < 0.003) and positive familial history of HCC (P: < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, beta-catenin mutations were associated with grade I (P: = 0.005) and stage I and II HCC (P: < 0.0001), and a better 5-year survival rate (P: = 0. 00003). These findings suggest mechanisms for beta-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that beta-catenin mutation is a favorable prognostic factor related to low stage. beta-Catenin mutation was associated with nuclear expression of the protein (P: < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear beta-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear beta-catenin had a better 5-year survival rate (P: < 0.007), suggesting that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent and deserve more studies for further clarification.
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PMID:Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. 1098 Jan 16

The pathogenesis of hepatitis C virus (HCV)-associated liver injury involves many genes from multiple pathogenic pathways. cDNA array analysis, which examines the expression of many genes simultaneously, was used to achieve new insights into HCV liver injury. Membrane-based cDNA arrays of 874 genes compared HCV-associated cirrhosis with autoimmune hepatitis-associated cirrhosis as an inflammatory and cirrhotic control, and with nondiseased liver tissue. Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signaling, apoptosis, and oxidative stress. Genes up-regulated in HCV-associated cirrhosis were predominantly associated with a Th1 immune response, fibrosis, cellular proliferation, and apoptosis. Novel observations of differential gene expression included increased expression of secreted apoptosis-related protein 3, a Wnt pathway gene possibly involved in cellular apoptosis. EMMPRIN (CD147) and discoidin domain receptor 1 (CD167) were also shown to be increased and are likely to play a role in liver fibrosis. Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed the increased expression of 15 genes. The comparison of HCV cirrhosis with autoimmune hepatitis cirrhosis showed a marked difference in the apoptosis-associated gene profile with HCV cirrhosis characterized by increased proapoptotic gene expression whereas autoimmune hepatitis was characterized by increased expression of both antiapoptotic and proapoptotic genes. Furthermore, expression of beta-catenin and the fibrosis-associated protein EMMPRIN were localized by immunohistochemistry to the plasma membranes of hepatocytes and biliary epithelium. In conclusion, HCV-associated cirrhosis was characterized by a proinflammatory, profibrotic, and proapoptotic gene expression profile.
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PMID:Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. 1183 85

Transgenic mice expressing the c-Myc oncogene driven by woodchuck hepatitis virus (WHV) regulatory sequences develop hepatocellular carcinoma with a high frequency. To investigate genetic lesions that cooperate with Myc in liver carcinogenesis, we conducted a genome-wide scan for loss of heterozygosity (LOH) and mutational analysis of beta-catenin in 37 hepatocellular adenomas and carcinomas from C57BL/6 x castaneus F1 transgenic mice. In a subset of these tumors, chromosome imbalances were examined by comparative genomic hybridization (CGH). Allelotyping with 99 microsatellite markers spanning all autosomes revealed allelic imbalances at one or more chromosomes in 83.8% of cases. The overall fractional allelic loss was rather low, with a mean index of 0.066. However, significant LOH rates involved chromosomes 4 (21.6% of tumors), 14, 9 and 1 (11 to 16%). Interstitial LOH on chromosome 4 was mapped at band C4-C7 that contains the INK4a/ARF and INK4b loci, and on chromosome 14 at band B-D including the RB locus. In man, the homologous chromosomal regions 9p21, 13q14 and 8p21-23 are frequently deleted in liver cancer. LOH at chromosomes 1 and 14, and beta-catenin mutations (12.5% of cases) were seen only in HCCs. All tumors examined were found to be aneuploid. CGH analysis of 10 representative cases revealed recurrent gains at chromosomes 16 and 19, but losses or deletions involving mostly chromosomes 4 and 14 generally prevailed over gains. Thus, Myc activation in the liver might select for inactivation of tumor suppressor genes on regions of chromosomes 4 and 14 in a context of low genomic instability. Myc transgenic mice provide a useful model for better defining crosstalks between oncogene and tumor suppressor pathways in liver tumorigenesis.
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PMID:Recurrent allelic deletions at mouse chromosomes 4 and 14 in Myc-induced liver tumors. 1189 80

The lack of good molecular markers for diagnosis as well as treatment assessment has rendered the hepatocellular carcinoma (HCC) a major challenge in health care. In this study, woodchucks were used as an animal model for hepatitis virus-induced HCC, and gene expression studies were performed using a human oligonucleotide microarray. An analysis approach combing supervised significant analysis of microarray (SAM), prediction analysis of microarray (PAM), and unsupervised hierarchical cluster methodologies statistically determined 211 upregulated and 78 downregulated genes between liver cancer and non-cancer liver tissues, and demonstrated > or = 93% accuracy in classifying the tissue samples. RT-PCR results confirmed the differential expression of selected sequenced woodchuck genes (SAT, IDH3B, SCD) in the microarray. Our study showed that differentially expressed genes were involved in transcription, RNA splicing, translation, cell cycle, metabolism, protein folding and degradation, apoptosis, immune response, metal binding, etc. Interestingly, some genes were involved with signaling pathways such as Ras/MAPK (MAPKAP1), Src-dependent pathways (CSK), hedgehog signaling pathway (HHIP), while Wnt signaling pathway may not be dominant in woodchuck HCC as shown by the downregulation of beta-catenin (TNNB1) and the upregulation of CXXC4 and CSNK2B. Numerous genes found in this study were also differentially expressed in human HCC and many other human cancers including breast, prostate and lung cancers, etc., serving as tumor suppressors, promoters, prognostic markers or chemotherapy targets. In conclusion, this study has demonstrated the robustness of the data analysis and the potential of using human microarrays on woodchuck samples. In particular, some of the differentially expressed genes in the woodchuck HCC can be further explored for possible molecular imaging targets or biological markers in human HCC.
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PMID:Gene expression studies of hepatitis virus-induced woodchuck hepatocellular carcinoma in correlation with human results. 1714 10

GB virus B (GBV-B) is the closest relative to hepatitis C virus (HCV) with which it shares a common genome organization, however, unlike HCV in humans, it generally causes an acute resolving hepatitis in New World monkeys. It is important to understand the factors regulating the different disease profiles of the two viruses and in this regard, as well as playing a key role in viral RNA replication, the HCV NS5A non-structural protein modulates a variety of host-cell signalling pathways. We have shown previously that HCV NS5A, expressed either alone, or in the context of the complete polyprotein, inhibits the Ras-extracellular-signal-regulated kinase (Erk) pathway and activates the phosphoinositide 3-kinase (PI3K) pathway. In this report, we investigate whether these functions are shared by GBV-B NS5A. Immunofluorescence analysis revealed that a C-terminally FLAG-tagged GBV-B NS5A exhibited a punctate cytoplasmic distribution. However, unlike HCV NS5A, the GBV-B protein did not partially co-localize with early endosomes. Utilizing a transient luciferase reporter system, we observed that GBV-B NS5A failed to inhibit Ras-Erk signalling, however GBV-B NS5A expression did result in the elevation of beta-catenin-dependent transcription via activation of the PI3K pathway. These effects of GBV-B and HCV NS5A on the PI3K and Ras-Erk pathways were confirmed in cells harbouring subgenomic replicons derived from the two viruses. Based on these data we speculate that the differential effects of the two NS5A proteins on cellular signalling pathways may contribute to the differences in the natural history of the two viruses.
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PMID:A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B. 1863 62

Under most circumstances, hepatitis B virus (HBV) is noncytopathic. However, hepatocellular regeneration that accompanies each bout of hepatitis appears to be associated with increased integration of HBV DNA fragments expressing the virus encoded hepatitis B x antigen (HBxAg). Intrahepatic HBxAg staining correlates with the intensity and progression of chronic liver disease (CLD), and additional work has shown that HBxAg blocks immune mediated killing by Fas and by tumor necrosis factor alpha (TNFalpha). This is not only associated with the blockage of caspase activities by HBxAg, but also by the constitutive stimulation of hepatoprotective pathways, such as nuclear factor kappa B (NF-kappaB), phosphoinositol 3-kinase (PI3K), and beta-catenin (beta-catenin). HBxAg also appears to promote fibrogenesis, by stimulating the production of fibronectin. HBxAg also stimulates the production and activity of transforming growth factor beta1 (TGFbeta1) by several mechanisms, thereby promoting the profibrogenic and tumorigenic properties of this important cytokine. In addition, HBxAg appears to remodel the extracellular matrix (ECM) by altering the expression of several matrix metalloproteinases (MMPs), which may promote tumor metastasis. Hence, HBxAg appears to promote chronic infection by preventing immune mediated apoptosis of infected hepatocytes, by promoting the establishment and persistence of fibrosis and cirrhosis preceding the development of HCC, and by promoting the remodeling of EMC during tumor progression.
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PMID:Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. 1920 Oct 80

The transition of epithelial cells to a mesenchymal phenotype is of paramount relevance for embryonic development and adult wound healing. During the past decade, the epithelial-mesenchymal transition (EMT) has been increasingly recognized to occur during the progression of various carcinomas such as hepatocellular carcinoma (HCC). Here, we focus on EMT in both experimental liver models and human HCC, emphasizing the underlying molecular mechanisms which show partial recurrence of embryonic programs such as TGF-beta and Wnt/ beta-catenin signaling, including collaboration with hepatitis viruses. We further discuss the differentiation repertoire of malignant hepatocytes with respect to the potential acquisition of stemness, and the involvement of the mesenchymal to epithelial transition, the reversal of EMT, in cancer dissemination and metastatic colonization. The strong evidence for EMT in HCC patients demands novel strategies in pathological assessments and therapeutic concepts to efficiently combat HCC progression.
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PMID:Epithelial-mesenchymal transition in hepatocellular carcinoma. 1985 28

A case of hepatocellular adenoma (HCA) was described in a 26-year-old woman, who was a potential kidney donor for her father and denied taking the oral contraceptive pill. A hypervascular mass of 4.1 cm in largest dimension was detected in the liver segment V by computerized tomography and magnetic resonance imaging (MRI). The normal levels of liver enzymes, negative serum markers for hepatitis viruses, and non-elevated alpha- fetoprotein level were detected. The wedge resection of segment V was done with an uneventful clinical course. In Western countries, HCAs are known to occur in women in their reproductive periods. It may not be associated with oral contraceptive. Molecular biological studies disclosed three variants of HCAs, i.e., I) with mutation of HNF 1-alpha gene, II) with mutation of beta-catenin gene, and III) no mutation of the two genes. Histological correlations with the three variants as recommended by the Bordeaux group in 2007 could not be accomplished in the present study due to overlapping histological features between the variants I and III. The etiological factors of HCA are known to relate to the contraceptive pill usage in female and the anabolic-androgenic-steroid administration in male. In Thailand, the occurrence of HCA is expected to be only 0.3% of cases with hepatocellular carcinoma.
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PMID:Hepatocellular adenoma: a case report. 2042 Jan 18


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