Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suppressor gene loci involved in the development of hepatocellular carcinoma (HCC) have not been fully identified. The aim of this study was to look for consistent allele loss, or loss of heterozygosity (LOH), in HCC which might represent such gene loci. We have prepared DNA from tumour and non-tumour material from 16 patients with HCC (nine with and seven without liver cirrhosis). Tumour DNA was compared with non-tumour DNA by Southern analysis performed with a panel of 22 probes recognising restriction fragment length polymorphisms assigned to chromosomes 1, 4, 5, 7, 9, 11, 12, 13, 14, 16, 17, 18 and 20. Non-tumour DNA from five of the seven patients with HCC without cirrhosis was heterozygous with the probe Lambda MS8 (5q35-qter), and in all five there was LOH in tumour DNA. Probes for other regions of chromosome 5 have as yet shown no LOH in this group of patients. Cirrhotic HCC patients exhibited LOH on chromosomes 1q and 5p but not in the region 5q35-qter. Both groups of HCC showed LOH on chromosome 17p13. Screening with other probes has not shown any consistent LOH in either group as yet. A comparison of LOH on chromosome 5 in seven patients with colorectal metastasis in the liver showed a different pattern, which suggests that the proposed tumour suppressor gene locus for HCC without cirrhosis on chromosome 5 appears to be distinct from the familial adenomatous polyposis coli gene.
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PMID:Loss of constitutional heterozygosity on chromosome 5q in hepatocellular carcinoma without cirrhosis. 168 7

Lysyl oxidase (EC 1.4.3.13), a copper-dependent enzyme which catalyses the formation of aldehyde cross-links, and acts primarily on collagen and elastin, is known to be increased during wound healing and in fibrotic disorders including liver cirrhosis and atherosclerosis, and to be decreased in some hereditary connective tissue diseases and in malignant cell lines. A recent study showed that lysyl oxidase might possess tumour suppressor activity as an antioncogene for ras. Little is known about the localization of this enzyme in human skin. In this study, we determined immunohistochemically the localization of lysyl oxidase in normal skin of young and elderly subjects obtained from sun-exposed and unexposed regions of the body. All skin samples tested had similar distributions of lysyl oxidase. The enzyme was present both extracellularly and intracellularly. Extracellularly, a few granular aggregates of immunoreactants were observed along collagen and elastic fibres. These granules were more common in the adventitial portion of the dermis than in the reticular portion. Of all sun-exposed and unexposed regions studied, the skin of the face displayed the greatest amount of extracellular immunoreactants. Immunopositive granules were observed intracellularly in fibroblasts, vascular endothelial cells, sweat glands, sebaceous glands, arrector pili muscles and some keratinocytes. These findings provide evidence that, as suggested in recent reports, lysyl oxidase may have a variety of intracellular functions.
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PMID:Immunohistochemical localization of lysyl oxidase in normal human skin. 791 5

To examine the significance of mutation of the p53 tumour suppressor gene in the development of human hepatocellular carcinoma in a high-prevalence area for hepatitis B viral infection but a low-exposure area for aflatoxin B1, the spectrum of p53 gene mutations was examined in 21 tumour samples from Hong Kong Chinese patients, all of whom were HBsAg positive. DNA sequencing covering exons 5 to 9 of the p53 gene and Hae III restriction enzyme digestion for preliminary assessment of mutation at codon 249 were performed. Immunohistochemical staining with anti-p53 monoclonal antibodies was done on both tumour and nontumour liver tissues. Six tumours (28.6%) showed a p53 mutation and all were point mutations. Of the six point mutations, two (9.5%) were at codon 249 and both were G to T transversions (AGG-->ATG and AGG-->AGT transversions). The remaining point mutations were transversions scattered at codon 172 (exon 5), 214 (exon 6), 273 (exon 8) and 330 (exon 9). Mutated p53 protein was detected in five of these six cases with demonstrable point mutations by DNA sequencing, in contrast to none detected in all of the 15 cases without demonstrable point mutations. The presence of p53 mutations, including those at codon 249, did not show a significant association with tumour size, sex, age, tumour invasiveness in terms of liver invasion, microsatellites and venous permeation, cirrhosis and encapsulation, but tumours with low cellular differentiation tended to have a higher incidence (71%) of point mutations than those with high cellular differentiation (8%). In conclusion, both the overall p53 mutation rate and that a codon 249 in HCC in Hong Kong Chinese are lower than those reported in tumours from China and sub-Saharan Africa. The low mutation rate at codon 249 is compatible with a low aflatoxin exposure. A special type of p53 mutation has not been found to be associated with hepatitis B viral infection. Mutations of p53 gene tends to occur in tumours with low cellular differentiation, suggesting a late occurrence in the event of tumour progression.
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PMID:p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese. 810 45

Some of the multiple factors involved in the molecular pathogenesis of hepatocellular carcinoma have been elucidated in recent years but no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Transformation of hepatocytes to the malignant phenotype may occur irrespective of the aetiological agent through a pathway of chronic liver injury, regeneration and cirrhosis. The activation of cellular oncogenes, the inactivation of tumour suppressor genes and overexpression of certain growth factors contribute to the development of HCC. There is increasing evidence that the hepatitis B virus may play a direct role in the molecular pathogenesis of HCC. Aflatoxins have been shown to induce specific mutations of the p53 tumour suppressor gene thus providing a clue to how an environmental factor may contribute to tumour development at the molecular level.
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PMID:The molecular pathogenesis of hepatocellular carcinoma. 879 May 56

In hepatocellular carcinoma (HCC) of patients from the Western hemisphere, mutations in the p53 tumour suppressor gene are present in up to 37% of cases. Conformational change and cellular accumulation can initiate an immune response with generation of circulating autoantibodies to p53 protein. In the present study, we investigated 711 consecutive patients with chronic liver disease to evaluate the sensitivity and specificity of autoantibodies to p53 protein as a serological marker for HCC. Detection of p53 autoantibodies was performed using an enzyme-linked immunosorbent assay with immobilised recombinant p53 protein. Liver cirrhosis was present in 259 patients (36.4%) and a HCC was diagnosed in 75 patients (10.6%). Autoantibodies to p53 protein were detectable in 15 of 377 patients with chronic liver disease (4.0%) and in 10 of 259 patients presenting with liver cirrhosis (3.9%). All 25 p53 autoantibody-positive/HCC-negative patients were carefully investigated and no underlying malignancy was clinically detected, suggesting that elevated p53 antibody levels may not exclusively be detectable in patients with malignant disease. In patients with clinically manifest HCC, p53 autoantibodies were detected in 17 of 75 cases, thus resulting in a sensitivity of 22.7% and a specificity of 96.1%. In contrast, assessment of serum alpha-fetoprotein (AFP) resulted in a sensitivity and specificity of 69.3 and 91.8% (AFP > 20 ng/ml) and 53.3 and 99.1% (AFP > 100 ng/ml) for the detection of HCC, respectively. The data of the present study reveal that the presence of p53 autoantibodies in patients with chronic liver disease is not completely specific for HCC. Moreover, we obtained no direct evidence that p53 autoantibody formation precedes the clinical diagnosis of HCC. However, serological screening for HCC might be improved by combining AFP and p53 autoantibody assays.
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PMID:Clinical evaluation of autoantibodies to p53 protein in patients with chronic liver disease and hepatocellular carcinoma. 984 79

Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the promutagenic DNA base lesion, O6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating agents such as N-nitroso compounds can produce O6-methylguanine in cellular DNA. Unrepaired, O6-methylguanine can lead to the formation of G --> A transition mutations, a known mechanism of human oncogene activation and tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte DNA. The paramount importance of O6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased hepatic levels of repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from animal models, this suggested a mechanism in which persistence of O6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of O6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively measure O6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular carcinoma.
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PMID:Repair of DNA lesion O6-methylguanine in hepatocellular carcinogenesis. 993 84

Mutations of p53 tumour suppressor gene often occur in hepatocellular carcinoma and, in particular, codon 249 hot-spot mutation is displayed by hepatocellular carcinomas occurring in hepatitis B virus-endemic areas with high dietary aflatoxin intake. This study was done to determine the frequency of p53 codon 249 mutation in hepato-cellular carcinoma in Nigerian patients with this tumour. Tumour samples were obtained from 18 Nigerian patients (all from the Southwest of the country) with histologically confirmed hepatocellular carcinoma by autopsy (n = 14), surgical resection (n = 3) and ante-mortem liver biopsy (n = 1). Fourteen of them had co-existing cirrhosis. Amplification of exon 7 of p53 gene from DNA samples of hepatocellular carcinoma tissue was undertaken by nested polymerase chain reaction followed by restriction enzyme analysis. One out of the 18 tumour samples tested (5.5%) demonstrated codon 249 mutation. This study suggests that, in Nigeria, especially the south-western region, aflatoxins appear to play a limited role in hepatocarcinogenesis.
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PMID:P53 codon 249 mutation in hepatocellular carcinomas from Nigeria. 1451 Jan 67

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer and is a common cancer type worldwide. Many aetiological factors have been related to HCC development, such as liver cirrhosis, hepatitis viruses and alcohol consumption. Inactivation of the p53 tumour suppressor gene is one of the most common abnormalities in many tumours, including HCC. p53 is of crucial importance for the regulation of the cell cycle and the maintenance of genomic integrity. In HCC, hepatitis B and C virus (HBV and HCV) effect carcinogenic pathways, independently leading to anomalies in p53 function. Several authors have reported that some HCV proteins, such as the core, NS5A and NS3 proteins, interact with p53 and prevent its correct function. The mechanisms of action of these HCV proteins in relation to p53 are not completely clear, but they might cause its cytoplasmic retention or accumulation in the perinuclear region where the protein is not functional. The identification of the interactions between p53 and HCV proteins is of great importance for therapeutic strategies aimed at reducing the chronicity and/or carcinogenicity of the virus.
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PMID:Hepatocellular carcinoma: molecular interactions between hepatitis C virus and p53 in hepatocarcinogenesis. 1498 3

The development of fibrosis and cirrhosis during chronic hepatitis B virus (HBV) infection correlates with the persistent expression of HBV x antigen (HBxAg), which acts in part, by stimulating selected signal transduction pathways, including nuclear factor kappa B (NF-kappa B). To identify NF-kappa B responsive genes that are differentially expressed in HBxAg-positive cells, HepG2 cells were stably transfected with HBxAg, and then with pZeoSV2 or pZeoSV2-I kappa B alpha. When RNAs from each culture were compared by PCR-select cDNA subtraction, fibronectin (FN) mRNA was shown to be strongly down-regulated by I kappa B alpha. Up-regulated expression of FN and co-expression between FN and HBxAg were observed in liver sections from HBV carriers that were stained for HBxAg and analysed for FN mRNA by in situ hybridization (ISH). In liver cell cultures, HBxAg increased the levels of FN mRNA and protein. This was because of the HBxAg-mediated trans-activation of the FN promoter, which was NF-kappa B-dependent. HBxAg also antagonized the repression of the FN promoter by the tumour suppressor, p53. Hence, the FN gene may be a natural target for HBxAg trans-activation, perhaps through activation of NF-kappa B and inactivation of p53, thereby contributing to the accumulation of FN in the liver over the course of chronic HBV infection.
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PMID:Activation of fibronectin gene expression by hepatitis B virus x antigen. 1523 Aug 56

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. The major aetiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. However, no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Malignant transformation of hepatocytes may occur as a consequence of various aetiologies, such as chronic viral hepatitis, alcohol, and metabolic disorders, in the context of increased cellular turnover induced by chronic liver injury, regeneration and cirrhosis. Activation of cellular oncogenes, inactivation of tumour suppressor genes, genomic instability, including DNA mismatch repair defects and impaired chromosomal segregation, overexpression of growth and angiogenic factors, and telomerase activation may contribute to the development of HCC. Overall, HCCs are genetically very heterogeneous tumours. New technologies, including gene expression profiling and proteomic analyses, should allow us to further elucidate the molecular events underlying HCC development and identify novel diagnostic markers as well as therapeutic targets.
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PMID:Pathogenesis of hepatocellular carcinoma. 1582 36


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