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)

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).
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PMID:P53 and proliferating cell nuclear antigen (PCNA) expression in non-tumoral liver diseases. 1033 76

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.
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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

Chronic hepatitis B progresses across a spectrum of asymptomatic carriers, active hepatitis, and liver cirrhosis. With more advanced disease stage, the risk for developing hepatocellular carcinoma (HCC) becomes higher. Recent studies suggest that this progressive risk may reflect an accumulation of multistage genetic mutations in the chromosomes of affected hepatocytes. Mutations of the known candidate genes such as p53 and beta-catenin have been found. Recent genome-wide analysis of HCC chromosomes by comparative genomic hybridization or loss of heterozygosity have identified more new loci implicated in hepatocarcinogenesis. Persistent hepatitis B is essential for inducing these mutations through immune-mediated injuries of the hepatocytes and the resulting hyperplasia. Prevention of hepatitis B by active immunization effectively interrupts persistent viral infections in children and subsequently reduces the risk of childhood HCC. Treatment for chronic hepatitis B by interferon or antiviral analogues can control hepatitis B activity, but its effect on controlling HCC remains to be seen. Insights for the hepatocarcinogenesis process should come from a multidisciplinary collaboration to explore important viral and host genes so that new approaches to diagnosis and treatment can be developed.
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PMID:Hepatitis B virus infection and hepatocellular carcinoma: molecular genetics and clinical perspectives. 1051 5

Previous research showed that risk factors associated with hepatocellular carcinoma (HCC) include infection with hepatitis B (HBV) and hepatitis C (HCV) viruses, exposure to aflatoxin B1 (AFB1), and liver cirrhosis, due primarily to alcohol consumption. To determine whether AFB1 may play a role in HCC in the United States, a search for AFB1 adducts and p53 alterations, potentially induced by AFB1, was conducted in the United States in 23 HCC patients with available tissue samples. The presence of AFB1 tumor-DNA and -serum lysine adducts and mutant p53 product was determined by immunoassays and codon 249 p53 mutation by restriction enzyme analysis. HBV and HCV serology and serum HBV-DNA were also determined. Thirteen patients were positive for HBV by HBs antigen or anti-HBc antigen or by polymerase chain reaction for HBV-DNA sequences. Nine patients were free of HBV and HCV markers; 5 of 22 sera tested were anti-HCV positive. p53 Protein expression, determined by immunohistochemical staining, was present in 5 of the 23 tumor tissues, whereas p53 codon 249 mutations were not observed in the 5 cases in which tissue was available for study. AFB1 tumor-DNA adducts were present in 3 of 19 tumor tissues, and in 1 of these 3 samples p53 protein was also detected. Sera from only 5 of the patients were tested for AFB1-lysine adducts, and all were positive. In these five patients, neither p53 protein nor a mutation on codon 249 was detected. The demonstration that AFB1-DNA and -lysine adducts are present in HCC patients in the United States is intriguing but requires further substantiation because of the small number of subjects in this pilot study. To elucidate the pathogenetic significance of these findings, further investigation, including studies in larger patient cohorts and properly selected controls, is warranted.
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PMID:Does aflatoxin B1 play a role in the etiology of hepatocellular carcinoma in the United States? 1062 3

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major risk factors for HCC development are now 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 etiologies, 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 tumor suppressor genes, overexpression of certain growth factors, and possibly telomerase activation and DNA mismatch repair defects may contribute to the development of HCC. Finally, aflatoxins have been shown to induce specific mutations of the p53 tumor suppressor gene, thus pointing to the contribution of environmental factors to tumor development at the molecular level.
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PMID:[Molecular aspects of hepatocellular carcinoma]. 1096 Sep 67

The worldwide incidence of hepatocellular carcinoma (HCC) is approximately one million cases a year. This makes HCC one of the most frequent human malignancies, especially in Asia and Africa, although the incidence is increasing also in the western world. HCC is a complication of chronic liver disease, with cirrhosis as the most important risk factor. Viral co-pathogenesis makes cirrhosis due to hepatitis B (HBV) and hepatitis C virus (HCV) infection a very important factor in the development of HCC. As curative therapy is often ruled out due to the late detection of HCC, it would be attractive to find parameters which predict malignant transformation in HBV- and HCV-infected livers. This study has used comparative genomic hybridization (CGH) to analyse 26 HCCs (11 non-viral, nine HBV, six HCV) and 12 concurrent dysplasias (five non-viral, five HBV, two HCV). Frequent gain (> or =25% of all tumours) was detected, in decreasing order of frequency, on 8q (69%), 1q (46%), 17q (46%), 12q (42%), 20q (31%), 5p (27%), 6q (27%), and Xq (27%). Frequent loss (> or =25% of all tumours) was found, in decreasing order of frequency, on 8p (58%), 16q (54%), 4q (42%), 13q (39%), 1p (35%), 4p (35%), 16p (35%), 18q (35%), 14q (31%), 17p (31%), 9p (27%), and 9q (27%). Minimal overlapping regions could be determined at multiple locations (candidate genes in parentheses). Minimal regions of overlap for deletions were assigned to 4p14-15 (PCDH7), 8p21-22 (FEZ1), 9p12-13, 13q14-31 (RB1), 14q31 (TSHR), 16p12-13.1 (GSPT1), 16q21-23 (CDH1), 17p12-13 (TP53), and 18q21-22 (DPC4, DCC). Minimal overlapping amplified sites could be seen at 8q24 (MYC), 12q15-21 (MDM2), 17q22-25 (SSTR2, GH1), and 20q12-13.2 (MYBL2, PTPN1). A single high level amplification was seen on 5q21 in an HBV-related tumour. Aberrations appeared more frequent in HBV-related HCCs than in HCV-associated tumours (p=0.008). This was most prominent with respect to losses (p=0.004), specifically loss on 4p (p=0.007), 16q (p=0.04), 17p (p=0.04), and 18q (p=0.03). In addition, loss on 17p was significantly lower in non-viral cancers than in HBV-related HCC (p<0.001). Furthermore, loss on 13q was more prevalent in HCCs in non-cirrhotic livers (p=0.02), thus suggesting a different, potentially more aggressive, pathway in neoplastic progression. A tendency (p=0.07) was observed for loss on 9q in high-stage tumours; no specific changes were found in relation to tumour grade. A subset of the HCC-associated genetic changes was disclosed in the preneoplastic stage, i.e. liver cell dysplasia. This group of dysplasias showed frequent gain on 17q (25%) and frequent loss on 16q (33%), 4q (25%), and 17p (25%). The majority of the dysplasias with alterations revealed genetic changes that were also present in the primary tumour. In conclusion, firstly, this study has provided a detailed map of genomic changes occurring in HCC of viral and non-viral origin, and has suggested candidate genes. Loss on 17p, including the TP53 region, appeared significantly more prevalent in HBV-associated liver cancers, whereas loss on 13q, with possible involvement of RB1, was distinguished as a possible genetic biomarker. Secondly, CGH analysis of liver cell dysplasia, both viral and non-viral, has revealed HCC-specific early genetic changes, thereby confirming its preneoplastic nature. Finally, genes residing in these early altered regions, such as CDH1 or TP53, might be associated with hepatocellular carcinogenesis.
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PMID:Molecular cytogenetic evaluation of virus-associated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias. 1100 97

Immunosuppression and transplantation have been reported to induce porokeratosis (PK), especially its variant, disseminated superficial PK (DSP). On the other hand, there is ample evidence of a relationship between hepatitis C virus (HCV) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). We report 3 cases of DSP in which the outbreak of DSP was suspected to have occurred during the development of HCC in patients with HCV-positive LC. The patients had undergone ultrasonographic study regularly, and no signs of malignancy had been found before the development of DSP. Their outbreaks of DSP were very acute, and the period between the development of DSP and diagnosis of HCC ranged from 2 to 6 months. The association of HCV-related HCC and DSP has never been previously reported. HCV-induced immunomodulation or its effect on the p53 system may be the basis for this type of association. It is necessary to consider development of HCC whenever DSP is found in HCV-positive patients. DSP may be a new paraneoplastic dermadrome.
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PMID:Synchronous development of disseminated superficial porokeratosis and hepatitis C virus-related hepatocellular carcinoma. 1104 35

Hepatobiliary neoplasms comprise a significant portion of the worldwide cancer burden. Advances in basic science research have led to rapid progress in our understanding of the molecular events responsible for these dreaded diseases. The genetic changes associated with hepatocellular carcinoma (HCC) have received the most attention. Aflatoxin B1 exposure leads to mutations in the p53 tumor suppressor gene, most commonly a transversion in codon 249 that leads to a substitution of serine for arginine in the p53 protein. Numerous other tumor suppressor genes, oncogenes, and tumor gene pathways are altered in HCC. Hepatitis B virus (HBV) infection is strongly associated with HCC. HBV may cause HCC either directly via the HBV X protein, or indirectly by causing liver inflammation and cirrhosis. Hepatitis C virus (HCV) infection is also associated with HCC. Recent evidence suggests that the HCV core protein may play a role in hepatocarcinogenesis. Several inherited metabolic diseases are associated with HCC. It is likely that these diseases cause HCC indirectly by causing cirrhosis. The molecular pathogenesis of cholangiocarcinoma and gallbladder cancer has not been well defined. However, multiple tumor suppressor genes and oncogenes, including p53 and K-ras, are altered in these tumors. Further molecular characterization of hepatobiliary tumors may lead to earlier diagnosis, better staging, improved treatment planning, and the development of more effective therapies.
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PMID:Genes and viruses in hepatobiliary neoplasia. 1112 84

The aim of this study was to identify the pattern and significance of expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. Histological sections from 18 patients with cholangiocarcinoma (3 of the cases were associated with primary sclerosing cholangitis), 10 patients with primary sclerosing cholangitis without cholangiocarcinoma, and 7 patients with cirrhosis without cholangiocarcinoma or primary sclerosing cholangitis were stained immunohistochemically for p53 and PCNA. Samples from 17 patients with cholangiocarcinoma (94%) stained positively for p53. Among these 17 cases, nontumorous bile duct epithelium was positive in 7 (including 3 cases with primary sclerosing cholangitis and 2 with carcinoma in situ), and were positive proliferating bile ductules in 4 cases. The single p53-negative cholangiocarcinoma did not show p53 positivity in either the bile duct epithelium or the proliferating bile ductules. Bile ductal and ductular cells in all 10 patients with primary sclerosing cholangitis without cholangiocarcinoma and in the 7 controls were not reactive for p53. All 18 samples from patients with cholangiocarcinoma (100%) were positive for PCNA protein. Bile duct epithelium was positive for PCNA in nine cases (90%) of primary sclerosing cholangitis without cholangiocarcinoma and in six (85%) controls. Our study showed a high rate of p53 expression (94%) in cholangiocarcinoma. The adjacent uninvolved bile duct epithelium was also immunoreactive for p53 in 7 of 17 patients (41%). These findings suggest an early p53 mutation in bile ductal cells in cholangiocarcinogenesis. Expression of p53 may potentially be used to identify or screen, by bile duct brushings, cases of primary sclerosing cholangitis suspected of harboring cholangiocarcinoma. Expression of PCNA was a universal feature in cholangiocarcinoma.
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PMID:Expression of p53 and PCNA in cholangiocarcinoma and primary sclerosing cholangitis. 1114 21

To analyze the aberrant expression of cell cycle-related proteins and their biological significance in relation to cirrhosis, we compared the cirrhotic patterns induced by two different types of cirrhotic agents, CCl4 and thioacetamide (TAA) in rats. CCl4 or TAA treatment was given to rats for 8 or 30 weeks, respectively, and the livers were removed at 9, 20, and 30 weeks after the experiment began. The TAA-induced fibrotic pattern was different from the CCl4-induced one, in terms of the formation of fibrous connective tissue and the proliferation of bile ductule cells. Cholangiofibrosis and clear cell foci were also observed in TAA-treated rats at 30 weeks. Histological examination revealed severe cirrhotic changes at 9 weeks in CCl4-treated rats and at 30 weeks in TAA-treated rats. Immunoblotting for cyclin D1, E, A, B, and proliferating cell nuclear antigen (PCNA) and their counterpart protein kinases (CDK2, 4, and CDC2) showed significant overexpression in rats with severely cirrhotic livers. The p53 tumor suppressor protein increased dramatically in the CCl4-treated group, while it was not detected in the livers of TAA-treated rats. Upregulation of p21WAF1, a CDK inhibitory protein, was detected in TAA-treated rats, but not in CCl4-treated rats. Immunohistochemical data for cyclin D1, E, and PCNA were well correlated with immunoblotting data; these proteins were increased in hepatocytes surrounding the cirrhotic lesions, suggesting that hepatocyte regeneration is correlated with cell cycle-related protein expression in cirrhotic liver. In the TAA-treated rats, the expression of these proteins was increased both in hepatocytes and in ductule cells. Our data suggest that liver cirrhosis induced by CCl4 or TAA is associated with alterations in cell cycle-related proteins, and that the expression of these proteins is responsible for hepatocyte regeneration in the damaged liver and may be involved in liver carcinogenesis.
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PMID:Expression patterns of cell cycle-related proteins in a rat cirrhotic model induced by CCl4 or thioacetamide. 1121 Dec 7


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