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

Human hepatitis B virus (HBV) is one of the causative agents of hepatocellular carcinoma (HCC). The virus encodes a 17 kDa protein, X, which is known to be a causative agent in the formation of HCC. An insulin-like growth factor-II (IGF-II) is expressed during the formation of HCC. Among the four promoters of the IGF-II gene, promoters 2, 3 and 4 become activated during the formation of HCC. The high frequency of detection of hepatitis B virus X (HBV-X) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that the expressions of HBV-X and IGF-II are associated. Studies were carried out to test the relationship between the HBV-X gene product and the activation of IGF-II promoter 4. We demonstrated that the HBV-X protein increases the endogenous IGF-II expression from promoter 3 and 4 of IGF-II gene. Analysis of the fourth promoter of IGF-II gene showed that the HBV-X gene product positively regulates transcription. Two copies of a motif are responsible for conferring HBV-X regulation on the fourth promoter of IGF-II. These motifs have been identified as Sp1 binding sites. Sp1 binding to IGF-II P4 promoter was identified by gel mobility shift assay using purified Sp1. By using a GAL4-Sp1 fusion protein it was demonstrated that HBV-X positively regulates the Spl mediated transcriptional activity of IGF-II in vivo. A protein-affinity chromatography experiment showed that HBV-X protein does not bind directly to Sp1, but HBV-X does augment the DNA binding activity of the phosphorylated form of Sp1 in HepG2 cells. Sp1 was phosphorylated by HBV-X and its DNA-binding activity was up-regulated upon HBV-X transfections. Various HBV-X mutant expression vectors were used for the demonstration of specific interactions between Sp1 and HBV-X. These results indicate that HBV-X functions as a positive regulator of transcription, and that Sp1 is a direct target for the transcriptional regulation of IGF-II. Increasing the DNA binding ability of the phosphorylated form of Sp1 by HBV-X might be an important mechanism for regulating the IGF-II gene expression and possibly promoting cell division during hepatic carcinogenesis. Our experimental results suggest that expression of HBV-X might induce the expression of IGF-II and the IGF-II might play a role in hepatitis B virus pathogenesis during the formation of HCC.
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PMID:The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor II promoter 4. 962 May 54

Cholesterol is used by cells for biosynthetic processes and for steroid synthesis. Although the role of cholesterol in tumorigenesis is not clear it is known that steroids are important factors in human carcinogenesis. A polypeptide, diazepam binding inhibitor (DBI), which is an endogenous ligand for peripheral benzodiazepine receptors enhances steroidigenesis by promoting cholesterol delivery to the inner mitochondrial membrane which represents the rate-limiting step of steroid biosynthesis. We have assayed the total cholesterol (TC) and the DBI plasma concentrations in patients with liver cirrhosis complicated by hepatocellular carcinoma (HCC) in comparison with those of uncomplicated liver cirrhosis. TC and DBI levels have been studied in 73 cirrhotic patients and in 23 patients with HCC. Both TC and DBI levels were higher in HCC patients when compared with age, sex and Child-Pugh class matched cirrhotic controls. The values (mean+/-S.D.) in patients in Child-Pugh class B and C with and without HCC were respectively 128+/-30 mg/dl vs. 106+/-27 mg/dl (P < 0.01) and 2.05+/-0.78 pmol/ml vs. 0.78+/-0.84 pmol/ml (P < 0.0001). The data may be the result of the metabolic influence of tumors that enhances steroid biosynthesis during tumor proliferation.
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PMID:Diazepam binding inhibitor and total cholesterol plasma levels in cirrhosis and hepatocellular carcinoma. 965 56

A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation.
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PMID:Alcohol and cancer. 975 43

Despite the recent development of percutaneous ethanol injection and liver transplantation, liver resection remains the reference treatment for hepatocellular carcinoma (HCC). The two drawbacks of this treatment are the risk associated with surgery and the high recurrence rate. Both are related to the almost constant presence of a chronic underlying liver disease. The risk of surgery has decreased significantly over the past 10 years and is currently less than 10%, even after a major hepatectomy, provided that cirrhosis is compensated (Child A) and that there is no superimposed chronic active hepatitis. Recurrence is usually related to de novo carcinogenesis Adjuvant and neoadjuvant therapies have no clearly demonstrated benefit. However, postoperative follow-up is mandatory as some recurrences are arnenable to local treatment, particularly rehepatectomy that has an efficacy comparable to that of first hepatectomy.
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PMID:[Surgical treatment of hepatocellular carcinoma in cirrhosis]. 975 3

Cancer risk in patients with cirrhosis could be modified by factors such as changes in hormonal levels, impaired metabolism of carcinogens, or alteration of immunological status. We investigated the risk of liver and various forms of cancer in patients with cirrhosis in a follow-up study. We identified 11,605 1-year survivors of cirrhosis from the files of the Danish National Registry of Patients (NRP) from 1977 to 1989. Occurrence of cancer through 1993 was determined by linkage to the Danish Cancer Registry. For comparison, the expected number of cancer cases was estimated from national age-, sex-, and site-specific incidence rates. Overall, 1,447 cancers were diagnosed among the study subjects, as compared with 708.1 expected, to yield a standardized incidence ratio (SIR) of 2.0 (95% CI: 1.9 to 2.2). In all diagnostic subgroups of cirrhosis, the risk of primary liver cancer, mainly hepatocellular carcinoma, was markedly elevated, with 245 observed cases and an overall 36-fold elevated risk (59.9-fold elevated for hepatocellular carcinoma and 10-fold for cholangiocarcinoma). Substantial and persistent excesses during follow-up were seen for all types of cancer associated with tobacco and alcohol habits (cancer of the lung, larynx, buccal cavity, pharynx, pancreas, urinary bladder, and kidney), while moderate excesses were seen for cancers of the colon and breast. The latter, however, were not complemented by any decrease in the risk of prostate cancer (SIR: 1.0; 95% CI: 0.7 to 1. 3). A slightly increased risk was seen for testis cancer, but disappeared after 10 years. We found evidence of an increased risk for liver and several extrahepatic cancers in patients with cirrhosis. Although part of this increase is likely attributable to alcohol and tobacco consumption, our study opens up the possibility that cirrhosis plays a role in the carcinogenesis of types of cancer other than liver cancer.
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PMID:Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. 975 26

Hepatitis B virus (HBV) is a small, enveloped DNA virus which primarily infects liver cells and causes acute and persistent liver disease. Chronic HBV infection, frequently associated with cirrhosis and eventually hepatocellular carcinoma (HCC), represents a major health problem in the world. HBV is the prototype member of the hepadnavirus family, which includes several related mammalian viruses also implicated in liver carcinogenesis in the host. Although epidemiological evidence has clearly linked HBV infection with HCC development, the precise role of the virus and the molecular mechanisms of liver cell transformation remain elusive. Here we discuss potential oncogenic strategies of HBV, ranging from indirect mechanisms related to chronic necroinflammatory disease and to the effects of viral gene products on cell proliferation and apoptosis, to direct insertional activation of cellular (onco)genes. Presently, vaccination of high risk populations represents a major way to prevent the development of HBV-related liver cancer.
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PMID:Hepatitis B viruses and cancerogenesis. 975 93

Polyamines (putrescine, spermidine and spermine) are essential for the proliferation of normal and neoplastic cells, and have been repeatedly recommended as tumor markers, with contrasting and elusive results. In the present study the urinary excretion of free and acetylated polyamines was measured in patients with hepatocellular carcinoma (HCC), cirrhotics and control subjects. Separation and quantification of dansyl-derivatives of free, acetylated and total polyamines was performed by reverse-phase high-performance liquid chromatography. The results show that the urinary excretion of total, free, and acetylated polyamines is significantly higher in HCC patients than in cirrhotics and controls (p < 0.001). The N1/N8 acetyl-spermidine molar ratio was found to be higher in HCC patients than in cirrhotics and controls (p < 0.001). No correlation was found between urinary excretion of polyamines and serum alpha-fetoprotein, tumor size and severity of liver cirrhosis. The results show that increased urinary excretion of free and acetylated polyamines, as well as an altered N1/N8-acetyl-spermidine molar ratio, is a sensible but not specific feature of HCC patients; polyamines may play a role in human carcinogenesis, but their determination does not seem reliable for the early detection of liver cancer.
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PMID:Urinary excretion of free and acetylated polyamines in hepatocellular carcinoma. 980 57

Ductular reaction refers to an increased number of ductules (the finest ramifications of the biliary tree), accompanied by polymorphonuclear leukocytes and an increase in matrix, leading to periportal fibrosis and eventually biliary cirrhosis. It is a phenomenon that is seen in a variety of liver diseases, such as acute and chronic cholestasis and variable degrees of parenchymal necrosis. Ductular reaction has gained new interest because of its relationship with putative human liver progenitor cells. The existence of progenitor cells in a quiescent organ such as the liver, although still controversial, is important for the understanding of biological processes, such as embryogenesis, carcinogenesis, and regeneration. This article provides a diagnostic algorithm: Starting from the phenomenon of ductular reaction, portal tract and parenchymal changes that give diagnostic clues are systematically described.
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PMID:Ductular reaction and its diagnostic significance. 984 27

Expression of p21 and c-myc protein in hepatocellular carcinomas and their surrounding liver tissue was detected on serial sections by immunohistochemical method. The results showed that the positive rates of p21 expression were 53.3% (16/30) and 96.7% (29/30) in hepatocellular carcinomas and pericarcinomatous liver tissue, and 40% (12/30) and 86.7% (26/30) and 86.7% (26/30) for c-myc protein expression respectively. Their incidences in pericarcinomatous liver tissue were higher than that in cancer tissue (P < 0.01). The patterns of p21 and c-myc protein in cells were cytoplasm, membrane and/or nuclear types. Their expression was more intensive in pericarcinomatous hepatocytes, especially in liver cirrhosis nodes. The results indicate that abnormal activiation and expression of oncogene ras and c-myc may be related to hepatocellular carcinogenesis.
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PMID:[Comparative study of expression of p21 and c-myc protein in hepatocellular carcinoma with pericarcinomatous liver tissue]. 986 83

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


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