Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic mice carrying the c-myc oncogene under control of woodchuck hepatitis virus (WHV) DNA sequences invariably develop hepatocellular carcinoma (HCC), despite a temporally limited expression of the transgene in the neonatal liver. To better characterize the different steps of the tumorigenic process, we analyzed the liver expression of the c-myc transgene and several growth-related genes by in situ hybridization and Northern blotting. In parallel studies, proliferated changes were investigated by detection of bromodeoxy-uridine-positive S-phase nuclei and apoptosis was evaluated by in situ nick end-labeling of DNA. During the neonatal period, high levels of c-myc messenger RNAs (mRNAs) were detected in all hepatocytes, and the expression of insulin-like growth factor II (IGF II) was frequently enhanced, correlating with increased cell proliferation. Despite elevated expression of the p53 gene, no change in liver cell apoptosis was observed. After weaning, c-myc transgene expression decreased to undetectable levels in all hepatocytes, whereas proliferation decreased but remained notably higher than in age-matched controls. The expression of c-fos, c-jun, and c-H-ras was highly variable during the preneoplastic period and in the tumors, with no consistent increase compared with controls. Resurgence of c-myc transgene expression was evidenced in all cells from hyperplastic lesions and carcinomas, accompanied with frequent focal reactivation of IGF II. Thus the strong proliferative stimulus induced by the combined effects of c-myc and IGF II in the neonatal liver might initiate a process characterized by persistent, dysregulated hepatocyte proliferation, in turn greatly increasing the risk of hepatocellular transformation.
 ...
PMID:Hepatocarcinogenesis in woodchuck hepatitis virus/c-myc mice: sustained cell proliferation and biphasic activation of insulin-like growth factor II. 909 91

Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFbeta. Moreover, p53-deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild-type cells. In vivo, p53-deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4-induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53-independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after gamma-irradiation of regenerating p53 null livers demonstrated circumstances where loss of G1 and G2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis. In that context, by reducing the need for cytokine support and disabling DNA damage-induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.
 ...
PMID:p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. 921 83

Chronic inflammatory states frequently lead to the increased production of nitric oxide (NO) via inducible NO synthase (NOS-2). In addition, NO may produce mutagenesis through several mechanisms such as DNA oxidation, DNA deamination, and the formation of N-nitroso compounds. As there is a strong association between human hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC), we were interested in whether human HCV hepatitis leads to induction of NOS-2 and if the mutation repair system of p53/p21 was upregulated. Reverse transcriptase-polymerase chain reaction (RT-PCR) for human NOS-2 message was performed on RNA samples from both liver biopsies and whole liver from HCV-positive and control patients (normal liver from hepatic resections for metastases). Immunohistochemistry (IHC) for p53 and Western blot analysis for p21 were also performed on the whole liver samples. From the liver biopsies, 60% of HCV-positive patients expressed NOS-2 by RT-PCR. Looking at the whole liver samples, 100% of the HCV-positive patients expressed NOS-2 vs 12.5% in the normal samples. p53 was not detected in either group but there was upregulation of p21 over baseline expression in a number of the HCV-positive patients. Human HCV hepatitis leads to consistent upregulation of hepatic NOS-2 message, but message is not predictably present in "normal" human liver. There is also induction of p21 in some patients with HCV hepatitis. Chronic expression of NO in HCV hepatitis may play a role in DNA mutagenesis and the development of HCC.
 ...
PMID:Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis. 922

Full length cDNAs for p53 were made by reverse transcription-polymerase chain reaction of total RNA from two normal woodchuck livers. Two randomly chosen clones from each liver were sequenced and shown to be identical. This sequence revealed 80% or more identity with p53 sequences from human, monkey, and mouse. The cDNA was translated into a 55 kD protein in vitro that was immunoprecipitated by antibodies to p53. Cotranslation of woodchuck p53 with woodchuck hepatitis virus X antigen, followed by immunoprecipitation suggested X/p53 complex formation. Similar complexes were also immunoprecipitated from extracts of infected liver, but not from uninfected liver. The finding of X/p53 complexes in vivo and in vitro in the woodchuck hepadnavirus system, combined with analogous data with hepatitis B, suggests a common mechanism by which these viruses contribute to hepatocellular transformation.
 ...
PMID:Partial characterization of the woodchuck tumor suppressor, p53, and its interaction with woodchuck hepatitis virus X antigen in hepatocarcinogenesis. 923 67

In HBV related hepatitis it is generally accepted that the liver injury is mediated by an immune response to the virus, since HBV is not directly cytopathic. The first step in cytotoxic T lymphocyte mediated immune reaction in HBV infected mice is the induction of apoptosis. The role of BCL-2, p53 and PCNA (as the main regulators of cell cycle homeostasis) in this process has not been studied. The aim of this pilot study is to estimate immunohistochemically the expression of the BCL-2, p53 and PCNA in a group of HBV infected patients at various stages of the disease. Formalin fixed, paraffin embedded liver biopsies from 5 patients with HBsAG positivity in their serum were used for immunohistochemical study of the expression of BCL-2, PCNA (PC10) and P53 (DO1clone). As the chromogen we used both the DAB and AEC. The results were co-related with the 3 liver biopsies as controls. In the hepatocytes of the all cases (including controls) we did not found any positivity of BCL-2, p53 and PCNA. However the majority of the lymphocytes present in the liver of some cases of HBV infected patients were strongly BCL-2 positive. This preliminary results of very small group of patients could indicate that hepatocytes in the HBV infection are in the quiescent stage as in the controls and that the cell cycle regulation during infection could be controlled by other genes such as bax, bcl-Xs, FAS etc., but further studies are required.
 ...
PMID:Immunohistochemical study of the expression of BCL-2, PCNA and P53 proteins in the patients with hepatitis B. The pilot study. 943

The tumor suppressor gene p53 is known to be involved in the negative regulation of cell growth. Proliferating cell nuclear antigen (PCNA), which is a nuclear protein and a component of the DNA replication process, is also involved in growth regulation. Both have been studied as progression markers in various tumors including hepatocellular carcinoma. In the present study, the aberrant p53 protein and PCNA expressions in non-tumoral liver diseases were investigated. Using monoclonal antibodies anti-p53 (D07-DAKO) and anti-PCNA (PC10-DAKO), 149 samples were stained, including 10 normal and 10 tumoral control liver tissues. p53 Overexpression was detected in 52 specimens (35%) whereas PCNA positivity was found in 96 (64%). There were 21 different pathological entities but most of the positive samples could be grouped into four types of diseases; namely, non-specific reactive hepatitis, steatohepatitis, chronic hepatitis and cirrhosis. Statistical analyses performed on these groups revealed that p53 positivity was found to be significantly higher in steatohepatitis (P < 0.05), while PCNA positivity did not show any statistical significance. The number of samples showing both p53 and PCNA positivity was 42 but their coexistence was not found to be significant. Certain cytological alterations like nuclear pleomorphism, steatosis and cholestasis, in addition to necroinflammatory activity, were evaluated for their possible impact on p53 and/or PCNA positivity. Necroinflammatory activity in steatohepatitis and steatosis in chronic hepatitis was found to be significant for p53 positivity (P < 0.05). In contrast, nuclear pleomorphism in non-specific reactive hepatitis was found to be significant for PCNA positivity (P < 0.05).
 ...
PMID:P53 and proliferating cell nuclear antigen (PCNA) expression in non-tumoral liver diseases. 1033 76

Vinyl chloride (VC) workers are known to be at risk for development of angiosarcoma of the liver (ASL), a rare tumor. Previously, a study of p53 gene mutations in tumors of VC-exposed workers found that 50% of liver angiosarcomas contained such mutations. Mutant p53 oncoprotein and anti-p53 antibodies can also be found in the sera of ASL patients and VC-exposed workers without cancer. Workers in Taiwan have also been exposed to VC, and some have contracted liver tumors. In this study, we used enzyme-linked immunosorbent assays to detect mutant p53 protein and anti-p53 antibodies in the plasma of VC-exposed workers in Taiwan. Thirty-three of 251 (13.2%) VC-workers tested positive for the p53 overexpression (10% with positive mutant p53 protein and 3.6% with positive anti-p53) in their plasma, but only 2 of 36 controls (5.6%) tested positive (2.8% with positive mutant p53 protein and 2.8% with positive anti-p53). There was a significant association between cumulative VC exposure concentration and positive p53 expression (P = 0.032) among VC workers after we adjusted for age, hepatitis, drinking, and smoking status. In summary, P53 overexpression (mutant p53 protein or anti-p53 antibody) can be found in the plasma of VC workers in Taiwan, and a significant dose-response relationship exists between plasma p53 overexpression and VC cumulative exposure concentration.
 ...
PMID:Plasma p53 protein and anti-p53 antibody expression in vinyl chloride monomer workers in Taiwan. 1039 Jul 5

The incidence of p53 gene abnormalities in human hepatocellular carcinoma (HCC) varies in different geographical areas, being higher in regions where hepatitis virus infection and dietary exposure to aflatoxin B1 are the most common aetiological agents. These mutations are less frequently encountered in Europe, although some studies have reported p53 protein overexpression in up to 45% of cases analysed. We have analysed 129 tumour samples of primary malignant hepatic neoplasms recovered from paraffin blocks processed in two pathology laboratories in a Mediterranean area of Spain (Valencia and Gerona). Among 14 cases in which p53 immunohistochemistry expression proved positive, 5 stained in more than 50% of the cell nuclei. By PCR-SSCP analysis we could detect the complete sequence from exon 5 through 8 in 70 cases and part of this region in the remaining cases, but no mutations were found. We found no relationship with the clinical stage, tumour stage or clinical outcome. We conclude that p53 gene alterations are not a major event in the malignant transformation of hepatic cells in this region of the Mediterranean. The variable incidence of p53 gene alterations in other geographical areas may reflect a different genetic background for the aetiology of HCC.
 ...
PMID:Absence of p53 gene mutations in hepatocarcinomas from a Mediterranean area of Spain. A study of 129 archival tumour samples. 1039 83

Accumulating evidence has demonstrated that aberration of the p53 tumour-suppressor gene is one of the pivotal genetic events in hepatocellular carcinogenesis. Recent reports suggest that the product of hepatitis B virus (HBV) interacts with p53 and that the hepatitis C virus (HCV) core protein reduces p53 expression. A novel p73 gene, which is related to p53, has recently been identified and mapped to chromosome 1p36.3, which is a locus of multiple tumour-suppressor genes for many cancers, including hepatocellular carcinoma (HCC) and neuroblastoma. Here, we investigated mRNA expression, allelotype and mutation of p73 in 48 HCCs obtained from untreated patients. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that p73 mRNA was expressed ubiquitously at low levels in all the tumour tissues, as well as in the adjacent normal liver tissues. The frequency of p73 loss of heterozygosity was observed in 20% of HCCs, but PCR-single strand conformation polymorphism (SSCP) analysis showed no mutations in the 48 tumours except for three types of polymorphisms. These results suggest that p73 may play a role in hepatocellular carcinogenesis in a different manner from a Knudson two-hit model. The regulatory mechanism of interaction between p73 and hepatitis viruses remains to be determined.
 ...
PMID:Absence of mutation of the p73 gene localized at chromosome 1p36.3 in hepatocellular carcinoma. 1040 9

We followed 145 men with chronic hepatitis B virus (HBV) hepatitis for 10 years to determine whether exposure to aflatoxin, or concomitant exposure to hepatitis C virus (HCV), or family history of hepatocellular carcinoma (HCC) increased the risk of developing HCC. We collected 8 monthly urine samples before beginning follow-up and pooled them to detect aflatoxin metabolite M1 (AFM1). AFM1 was detected in 78 (54%) of the subjects. The risk of HCC was increased 3.3-fold (with a 95% confidence interval of 1.2-8.7) in those with detectable AFM1 (above 3.6 ng/L). This relative risk was adjusted for age and for HCV status. The attributable risk from exposure to detectable AFM1 was 0.553 (0.087, 0.94). The relative risk of fatal cirrhosis for those with elevated AFM1 was 2.8 (0.6, 14.3), and the odds of having a persistently elevated alanine transaminase (ALT) were 2.5-fold greater in those with detectable AFM1 (P =.007). Concomitant infection with HCV increased the risk of HCC 5.8-fold (2. 0-17), adjusted for age and AFM1 status. A family history of HCC increased the risk of HCC 5.6-fold, adjusted for age and AFM1. Four men with detectable AFM1 and HCC all had missense mutation in codon 249 of the p53 gene in cancer tissues. This study shows that exposure to AFM1 can account for a substantial part of the risk of HCC in men with chronic HBV hepatitis and adds importantly to the evidence that HCV and family history of HCC increase the risk of HCC in men with chronic HBV hepatitis.
 ...
PMID:Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. 1042 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>