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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Human E-cadherin is a homophilic cell adhesion molecule and its expression is well preserved in normal human hepatocytes; a decrease in its expression has been observed in poorly differentiated hepatocellular carcinoma cells. We examined the alteration of E-cadherin and catenin expressions caused by differentiation inducers in human hepatocellular carcinoma cells. Hepatocellular carcinoma cell lines, HCC-T and HCC-M, were cultured with all-trans retinoic acid (ATRA), dexamethasone (DEX), sodium butyrate, and interferon-alpha. E-cadherin expression was only up-regulated by butyrate and interferon-alpha (IFN-alpha) in both cell lines, studied by means of fluorescence immunostaining and flow cytometry. The localization of E-cadherin staining was shown at their cell membrane. According to the increase in E-cadherin expression, beta-catenin expression appeared at the cell membrane of both cell lines when treated with butyrate and IFN-alpha. Such an appearance was not observed when cells were treated with ATRA and DEX. Western blotting showed that alpha- and y-catenin expression was not changed, while only the expression of beta-catenin increased. Beta-catenin oncogenic activation as a result of amino acid substitutions or interstitial deletions within or including parts of exon 3, which has been demonstrated recently, was not detected in these cell lines by direct deoxyribonucleic acid sequencing. These results suggest that the expression and interaction between E-cadherin and wild-type beta-catenin are potentially modulated by butyrate and IFN-alpha, and that these two agents are potent inhibitors of hepatocellular carcinoma cell invasion and metastasis.
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PMID:Up-regulation of E-cadherin and I-catenin in human hepatocellular carcinoma cell lines by sodium butyrate and interferon-alpha. 1094 98

Inactivation of the p16INK4a (p16) tumor suppressor gene by promoter hypermethylation and mutation within exon 3 of beta-catenin represent two of the more common gene alterations in human hepatocellular carcinoma (HCC). One exposure implicated in the development of liver cancer is hepatitis B or C viral infection, which causes chronic destruction and regeneration of liver parenchyma. Treatment of rats with high doses of the tobacco-specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) also causes liver toxicity and a high incidence of tumors. The purpose of the current investigation was to define the prevalence of genetic alterations in p16 and beta-catenin in NNK-induced rat liver cancer to determine if the molecular mechanisms seen in human tumors are the same in this animal model. DNA isolated from 15 adenomas and 14 carcinomas was examined for methylation of p16 by methylation-specific PCR. p16 methylation was detected in five of 15 adenomas and eight of 14 carcinomas (45% of all tumors). Methylation of p16 was extensive within the 5'-untranslated region and exon 1alpha, areas shown to correlate with loss of gene transcription. Liver tumors were also screened for mutations within exon 3 of beta-catenin. Single strand conformation polymorphism and DNA sequencing revealed five mutations in four of 29 tumors (14%). Mutations were present in three adenomas and one carcinoma and were located within codons 33, 36 or 37. All mutations resulted in amino acid substitutions; three of these mutations occurred at potential serine phosphorylation sites. Our results link two important regulatory pathways altered in human HCC to cancer induced in the rat NNK model. The fact that common genetic alterations are observed between rodent and human HCC suggests that the rat NNK model could be useful for identifying additional genetic alterations critical to the initiation of HCC.
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PMID:p16INK4a and beta-catenin alterations in rat liver tumors induced by NNK. 1123 87

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

It is still unclear as to whether the gene expression profile in HCV- or HBV-related HCC exhibits a degree of specificity and whether the development of HCC in a context of cirrhosis influences this gene profile. To address these issues, the expression profiles of 15 cases of HCC were analysed using cDNA macroarray. A global analysis and hierarchical clustering, demonstrated the heterogeneity of HCC patterns, with a majority of down-regulated genes. Statistical analysis clearly showed a distinction between the gene expression profiles of HCV- and HBV-related HCC. HBV-associated HCC exhibited involvement of different cellular pathways, those controlling apoptosis, p53 signalling and G1/S transition. In HCV-related HCC we identified a more heterogenous pattern with an over-expression of the TGF-beta induced gene. In HCC developing on non-cirrhotic tissues, beta-catenin encoding gene and genes implicated in the PKC pathway were specifically up-regulated. In addition, our investigation highlighted a distinct profiles of TGF-beta superfamily encoding genes in well, moderately or poorly differentiated HCC. Overall, our study supports the hypothesis that despite the heterogeneity of the HCC pattern, the large-scale screening of gene expression may provide data significant to our understanding of the mechanism of liver carcinogenesis.
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PMID:Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. 1197 55

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. Chronic infections with the hepatitis B virus (HBV) and the hepatitis C virus (HCV) have been implicated in about 80% of cases worldwide, and other known environmental risk factors, including alcohol abuse and dietary intake of aflatoxin B1, might synergize with viral infections. Recent insight into the molecular mechanisms leading to HCC development has been provided by the identification of major genetic abnormalities revealed by genomewide allelotype studies and molecular cytogenetic analysis. Moreover, several oncogenic pathways have been implicated in malignant transformation of liver cells. Inactivation of the p53 tumor suppressor gene by mutations and allelic deletions in about 30% of HCC cases has been associated predominantly with exposure to aflatoxin B1 and HBV infection. By contrast, a mutation in the beta-catenin gene in around 22% of HCCs is more rare in HBV-associated tumors. Activation of cyclin D1 and disruption of the Rb pathway are also commonly involved in liver tumorigenesis. New major challenges include the identification of candidate genes located in frequently altered chromosomal regions and that of oncogenic pathways driven by different risk factors. This search might shed some light on the tumorigenic role of HBV and HCV. It might also permit accurate evaluation of major targets for prognostic and therapeutic intervention.
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PMID:Genetic alterations and oncogenic pathways in hepatocellular carcinoma. 1209 25

We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.
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PMID:Analysis of the beta-catenin/T cell factor signaling pathway in 36 gastrointestinal and liver cancer cells. 1246 Apr 62

Liver cancer is one of the major human tumors in the world. Basic and epidemiological studies have proposed that the major risk factors for liver cancer include alcohol and diet as well as infection with hepatitis B and C viruses. However, the mechanistic clues for the development of this type of cancer is largely unknown. Poly(ADP-ribose) polymerase (PARP-1) and a component of nonhomologous end-joining (NHEJ) machinery, Ku80, are two major DNA end-binding molecules that play a multifunctional role in DNA damage signaling and repair, recombination as well as the maintenance of genomic stability. Here we show that the interaction of PARP-1 and Ku80 is essential for development because PARP-1/Ku80 double null mice died at embryonic day (E) 9.5. Interestingly, haplo-insufficiency of Ku80 in PARP-1-/- mice promotes the development of hepatocellular adenoma and hepatocellular carcinoma (HCC). These tumors exhibited a multistage tumor progression associated with the loss of E-cadherin expression and the mutation of beta-catenin. Cytogenetic analysis revealed that Ku80 heterozygosity elevated chromosomal instability in PARP-1-/- cells and that these liver tumors harbored a high degree of chromosomal aberrations including fragmentations, end-to-end fusions, and recurrent nonreciprocal translocations (NRT). These features are reminiscent of human HCC. Taken together, these data implicate a synergistic function of Ku80 and PARP-1 in minimized chromosome aberrations and cancer development and suggest that defects in DNA end-processing molecules may be etiological factors in human HCC formation.
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PMID:Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. 1246 Sep 17

Wnt signaling mediated by beta-catenin plays crucial roles in the development of hepatocellular carcinoma and other cancers such as colorectal cancer. beta-Catenin associates with T-cell factor (TCF) transcription factors and functions as a transcriptional activator in the nucleus. By protein interaction screening, we identified EBP50, a cytoplasmic protein with 2 PDZ domains, as a beta-catenin-associating molecule. EBP50 interacted with beta-catenin through its carboxyl-PDZ domain in vitro and in vivo. Northern blot and RT-PCR analysis revealed an increase of EBP50 messenger RNA (mRNA) in hepatocellular carcinoma (HCC) cell lines and surgical specimens of human HCC. Over-expression of EBP50 protein with focal nuclear localization was detected in human HCC. In human HCC and colorectal cancer cell lines, EBP50 enhanced beta-catenin/TCF-dependent transcription in a dose-dependent manner. In an HCC cell line, over-expression of the carboxyl PDZ domain resulted in a decrease of endogenous beta-catenin/TCF transactivation. EBP50 promoted beta-catenin-mediated transactivation only in cells in which beta-catenin was already stabilized, suggesting that EBP50 may work with stabilized beta-catenin for transcriptional regulation. In conclusion, the EBP50/beta-catenin complex promotes Wnt signaling, and over-expression of EBP50 may work cooperatively with beta-catenin in the development of liver cancer.
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PMID:EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. 1283

Heterocyclic amines are potent mutagens and carcinogens formed in cooked protein rich foods. In this study, we screened liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) in CDF1 mice for beta-catenin and APC mutations and other genetic alterations shown to occur in human hepatocellular carcinomas (HCC), including mutations in the p53 and H-ras genes, c-myc amplification and E-cadherin promoter methylation. SSCP followed by direct DNA sequencing revealed mutations in exon 2 of the beta-catenin gene in 2 of 16 liver tumors (12.5%). Promoter methylation of the E-cadherin gene was detected in one liver tumor induced by MeIQ. There were no mutations in the mutation cluster region of the APC gene, in exons 5-8 of the p53 gene, or in codons 12, 13 and 61 of the H-ras gene, nor c-myc amplification in any of liver tumors induced by MeIQ. These data indicate that except for the occasional disruption of the Wnt pathway through beta-catenin mutations, the genetic pathways involved in the development of HCC differ significantly between human liver cancer and tumors induced in mice by MeIQ, but do not rule out the possibility that heterocyclic amines constitute a carcinogenic risk factor in humans.
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PMID:Beta-catenin mutations in liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in CDF1 mice. 1289 27


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