Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene therapy using replication-competent adenovirus that selectively propagates in tumor cells may be an effective treatment for cancer. We developed an adenovirus that would be replication specific for hepatocellular carcinoma (HCC). Based on our finding that the E1B55k-deficient adenovirus was able to replicate in human primary hepatocytes, we therefore designed an adenovirus carrying E1A and attenuated E1B gene driven by the alpha-fetoprotein promoter (Adv-AFP-E1AdB), thus restricting the replication specificity in AFP-producing HCC. Replication of Adv-AFP-E1AdB in primary hepatocytes was practically negligible 4 days after infection. Although Adv-AFP-E1AdB replicated slowly in AFP-producing HCC, it efficiently destroyed HCC cells independent of their p53 status. Experiments were conducted in vivo using systemic administration of Adv-AFP-E1AdB and we observed tumor size reduction in nude mice having liver cancer. The use of replication-competent adenovirus deficient of the E1B gene coupled to an AFP-targeting strategy may be a safe and efficacious treatment for HCC.
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PMID:Target gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by E1B55k-attenuated adenovirus. 1140 92

The X-gene product of hepatitis B virus (HBx) has been implicated in hepatitis B virus (HBV)-mediated hepatocellular carcinoma through its ability to induce liver cancer in some transgenic mice and to transactivate a variety of viral and cellular promoters. In this study, we demonstrated that the level of p21(waf1) RNA was decreased in the HBx-expressing cells and this effect was due to the transcriptional repression of the p21(waf1) gene by HBx via a p53-independent pathway. As the Sp1 binding sites of the p21(waf1) promoter were sufficient to confer HBx responsiveness to a previously non-responsive promoter, we suggested that HBx represses the transcription of p21(waf1) by downregulating the activity of Sp1. Because the tumor repressor p21(waf1) protein is a universal inhibitor of cyclin-CDK complexes and DNA replication that induces cell cycle arrest at the G1-S checkpoint, the repression of p21(waf1) by HBx might play an important role in a HBV-mediated pathogenesis.
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PMID:Transcriptional repression of p21(waf1) promoter by hepatitis B virus X protein via a p53-independent pathway. 1157 65

To evaluate current knowledge on the multicentric occurrence (MO) of hepatocellular carcinoma (HCC) and its clinical significance was the purpose of this review. The criteria for MO of HCC are defined as follows: (1) the recurrent tumor consists of well differentiated HCC occurring in a different hepatic segment from moderately or poorly differentiated preexisting HCC, (2) both the primary and recurrent tumors are well differentiated HCC, (3) the recurrent tumors contain regions of dysplastic nodules in peripheral areas and, (4) multiple HCCs, indicating the "nodule-in-nodule" form, in which nodules consisting of moderately or poorly differentiated HCC cells are contained in a nodule of well differentiated HCC cells. However, these criteria assume rare or no metastasis of well differentiated HCC, and are also not applicable to cases in which some HCCs of multicentric origin are rapidly dedifferentiated, presenting morphologic features of moderately or poorly differentiated tumors. Diagnostic methods, besides histopathologic methods, for determining multicentric origin in multiple HCCs in the liver, or recurrent tumor(s) of HCC, include clonal analysis of the integration pattern of hepatitis B virus (HBV) DNA in HBV carrier patients, and analysis of the p53 mutation patterns or loss of heterozygosity of chromosomal DNA. The prognosis of patients with MO of HCC after curative resection is significantly better than that of patients with intrahepatic HCC metastasis. Moreover, the Liver Cancer Study Group of Japan has reported that patients with hepatic resection for small-sized HCCs showed higher survival rates than a nonsurgical treatment group. Consequently, HCC with MO, whether this is synchronous or metachronous, should be surgically removed as the treatment of first choice.
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PMID:Multicentric occurrence of hepatocellular carcinoma: diagnosis and clinical significance. 1170 53

We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.
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PMID:Alpha-particle carcinogenesis in Thorotrast patients: epidemiology, dosimetry, pathology, and molecular analysis. 1179 40

Tumor suppressor p53 is known to inhibit transactivation by certain nuclear receptors, and overexpressed p53 is known to correlate with poor differentiation in liver cancer. Therefore, we investigated whether wild-type p53 might also affect the function of hepatocyte nuclear factor 4alpha1 (HNF4alpha1), an orphan receptor required for liver differentiation. Our results show that HNF4alpha1-mediated transactivation is repressed by p53 but that the mechanism of repression is not due to inhibition of HNF4alpha1 DNA binding. Rather, transfections with Gal4 fusion constructs indicate that the repression is via the ligand-binding domain of HNF4alpha1. Furthermore, we found that p53 in human embryonic kidney whole-cell extracts preferentially bound the ligand-binding domain of HNF4alpha1 and that the activation function 2 region was required for the binding. Competition for coactivator CREB binding protein could not entirely account for the repression but trichostatin A, an inhibitor of histone deacetylase activity, could reverse p53-mediated repression of HNF4alpha1. In contrast, p53-mediated repression of transcriptional activation of the same promoter by another transcriptional activator, CCAAT/enhancer-binding protein-alpha, could not be reversed by the addition of trichostatin A. These results suggest that p53, like other transcriptional repressors, inhibits transcription by multiple mechanisms, one of which involves interaction with the ligand-binding domain and recruitment of histone deacetylase activity.
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PMID:Repression of hepatocyte nuclear factor 4alpha tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity. 1181 10

AIM:To study hepatocarcinogenesis of hepatitis C virus (HCV).METHODS: Expression of HCV antigens (CP10, NS3 and NS5) and several cancer-associated gene products (ras p21, c-myc, c-erbB-2, mutated p53 and p16 protein) in the tissues of hepatocellular carcinoma (HCC, n = 46) and its surrounding liver tissue were studied by the ABC(avidin-biotin complex) immunohistochemical method. The effect of HCV infection on expression of those gene products in HCC was analyzed by comparing HCV antigen positive group with HCV antigen negative group.RESULTS:Positive immunostaining with one, two or three HCV antigens was found in 20 (43.5%) cases,with either of two or three HCV antigens in 16 (34.8%) cases, and with three HCV antigens in 9 (19.6%) cases.Deletion rate of p16 protein expression in HCC with positive HCV antigen (80%, 16/20)was significantly higher than that in HCC with negative HCV antigen. Whereas no significant difference of the other gene product expression was observed between the two groups.CONCLUSION:HCV appears related to about one third of cases of HCC in Chongqing, the southwest of China, and it may be involved in hepatocarcinogenesis by inhibi ting the function of p16 gene, which acts as a negative regulator of cell cycle.
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PMID:Effect of HCV infection on expression of several cancer-associated gene products in HCC. 1181 78

p21(WAF1/CIP1) is a universal cyclin-dependent kinase inhibitor. To investigate the role of p21(WAF1/CIP1) in proliferation of human liver cancer cells, we examined the expression of p53, p21(WAF1/CIP1), cdk2 and cdk4 expression in two human liver cancer cell lines (HepG2 and PLC/PRF/5 cells). The effects of p21(WAF1/CIP1) on [(3)H]thymidine incorporation and cdks were also examined in these cells. HepG2 cells expressed all these proteins with lower level of cdk4. PLC/PRF/5 cells expressed the other proteins except p21(WAF1/CIP1). Transfection of p21(WAF1/CIP1) gene inhibited [(3)H]thymidine incorporation of both cells with different extent. Although the transfection of p21(WAF1/CIP1) did not affect cdk2 and cdk4 expression, it did reduce cdk2 kinase activity by 20%. These results suggest that: (a) p21(WAF1/CIP1) involved in DNA synthesis of human liver cancer cells; (b) p21(WAF1/CIP1) could be a target gene for the treatment of human hepatocellular carcinoma.
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PMID:A cyclin-dependent kinase inhibitor (p21(WAF1/CIP1)) affects thymidine incorporation in human liver cancer cells. 1187 May 47

Although resection is currently the only curative approach for metastatic liver cancer, only a small number of cases are suitable for this procedure. In the past few years, gene therapy has emerged as an appealing treatment option for liver cancer. Phase I and II clinical trials have been conducted in patients with either primary or secondary liver cancer using a variety of genes including tumor-suppressor gene p53, suicide genes, immune genes, and replication-competent oncolytic adenoviruses. The results have shown that, although gene therapy has been well tolerated and toxicity has been low, the clinical benefit has so far been marginal. Gene therapy as a definitive treatment for liver metastases remains limited, at least for the time being, but it may be useful as an adjuvant treatment in combination with radiotherapy, chemotherapy, and/or surgery to achieve disease-free survival.
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PMID:Gene therapy for liver metastases. 1195 Dec 19

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

A G to T mutation has been observed at the third position of codon 249 of the p53 tumor-suppressor gene in over 50% of the hepatocellular carcinoma cases associated with high exposure to aflatoxin B(1) (AFB(1)). Hypotheses have been put forth that AFB(1), in concert with hepatitis B virus (HBV), may play a role in the formation of, and/or the selection for, this mutation. The primary DNA adduct of AFB(1) is 8,9-dihydro-8-(N(7)-guanyl)-9-hydroxyaflatoxin B(1) (AFB(1)-N7-Gua), which is converted naturally to two secondary lesions, an apurinic site and an AFB(1)-formamidopyrimidine (AFB(1)-FAPY) adduct. AFB(1)-FAPY is detected at near maximal levels in rat DNA days to weeks after AFB(1) exposure, underscoring its high persistence in vivo. The present study reveals two striking properties of this DNA adduct: (i) AFB(1)-FAPY was found to cause a G to T mutation frequency in Escherichia coli approximately 6 times higher than that of AFB(1)-N7-Gua, and (ii) one proposed rotamer of AFB(1)-FAPY is a block to replication, even when the efficient bypass polymerase MucAB is used by the cell. Taken together, these characteristics make the FAPY adduct the prime candidate for both the genotoxicity of aflatoxin, because mammalian cells also have similar bypass mechanisms for combating DNA damage, and the mutagenicity that ultimately may lead to liver cancer.
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PMID:The aflatoxin B(1) formamidopyrimidine adduct plays a major role in causing the types of mutations observed in human hepatocellular carcinoma. 1201 30


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