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)

One of the major antecedent factors preceding the development of hepatocellular carcinoma is chronic hepatitis B virus infection. Also, recent molecular studies have shown that activation of c-oncogenes might be responsible for the malignant transformation in some cases of hepatocellular carcinoma. We used immunohistochemical methods to investigate the correlation of ras and c-myc oncogene expression with the presence of HBsAg in human liver disease. Our material consisted of 23 chronic active hepatitis B needle liver biopsies and surgical specimens from 11 cases of cirrhosis, 23 hepatocellular carcinoma and 10 normal adult livers. Direct, three-step and streptavidin-biotin-complex immunoperoxidase techniques using polyclonal (anti-HBsAg) and monoclonal antibodies (anti-ras p21, anti-myc p62), were performed. Normal liver tissues were negative for all antibodies used. In HBsAg+ chronic active hepatitis B cases enhancement of c-myc, and less frequently of ras oncogene expression, was a common observation. Increased myc p62 and ras p21 expression was a finding not restricted to HBsAg+hepatocytes, which occasionally were negative for oncoprotein immunostaining. All HBsAg-chronic active hepatitis B cases were negative for ras p21 and myc p62 specific staining. Cirrhotic livers showed more frequently enhanced c-myc expression. Most of the immunostained cells were negative for HBsAg. HBsAg- cases of hepatocellular carcinoma more often showed ras p21 than myc p62 overexpression. HBsAg+ hepatocellular carcinomas presented only ras p21-positive immunostaining, which was not detected in HBsAg+ hepatocytes. Our recent data supports the view that continued expression of HBsAg in human liver disease is not necessary for the enhancement of ras and c-myc oncogene expression.
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PMID:Expression of ras and c-myc oncoproteins and hepatitis B surface antigen in human liver disease. 846 26

In hepatocellular carcinoma (HCC), autoantibodies to intracellular antigens are detected in 30-40% of patients. Patients with chronic hepatitis or liver cirrhosis develop HCC, and when this occurs, some patients exhibit autoantibodies of new specificities. It has been suggested that these novel autoantibody responses may be immune system reactions to proteins involved in transformation-associated cellular events. One HCC serum shown to contain antibodies to unidentified cellular antigens was used to immunoscreen a cDNA expression library, and a full length cDNA clone was isolated with an open reading frame encoding 556 amino acids with a predicted molecular mass of 62 kD. The 62-kD protein contained two types of RNA-binding motifs, the consensus sequence RNA-binding domain (CS-RBD) and four hnRNP K homology (KH) domains. This protein, provisionally called p62, has close identity (66-70%) to three other proteins at the amino acid sequence level, and all four proteins may belong to a family having CS-RBD in the NH2-terminal region and four KH domains in the mid-to-COOH- terminal region. The homologous proteins are: KH domain-containing protein overexpressed in cancer (Koc); zipcode binding protein, a protein which binds to a conserved nucleotide element in chicken beta-actin mRNA (ZBP1); and a protein which binds to a promoter cis element in Xenopus laevis TFIIIA gene (B3). p62 protein is cytoplasmic in location, and autoantibodies were found in 21% of a cohort of HCC patients. Patients with chronic hepatitis and liver cirrhosis, conditions which are frequent precursors to HCC, were negative for these autoantibodies, suggesting that the immune response might be related to cellular events leading to transformation. However, the possible involvement of p62 autoantigen as a factor in the transformation process remains to be elucidated.
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PMID:A novel cytoplasmic protein with RNA-binding motifs is an autoantigen in human hepatocellular carcinoma. 1019 Sep 1

A feature of hepatocellular carcinoma (HCC) is that antecedent liver cirrhosis and chronic hepatitis are common precursor conditions and during transition to malignancy some patients develop autoantibodies which were not present during the preceding chronic liver disease phase. Serum samples from such patients can be used to immunoscreen cDNA expression libraries to identify genes encoding the new autoantigens. We demonstrate here the de novo appearance of antibodies to p62, a cytoplasmic protein which has been shown to bind to a developmentally regulated fetal species of insulin-like growth factor II (IGF-II) mRNA. Another antibody appearing during the transition period was against CENP-F, a cell cycle-related nuclear protein with maximum expression in the G2 and M phases of the cell cycle and previously shown to have a high association with malignancy. In three additional patients in whom serial serum samples were examined, new appearance of anti-p62 was detected in two patients and anti-CENP-F in one patient. This study demonstrates that transition to malignancy can be associated with autoantibody responses to certain cellular proteins which might have some role in tumorigenesis.
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PMID:De-novo humoral immune responses to cancer-associated autoantigens during transition from chronic liver disease to hepatocellular carcinoma. 1147 19

p62 is a RNA-binding protein that was isolated by immunoscreening a cDNA expression library with autoantibodies from patients with hepatocellular carcinoma (HCC). This autoantigen binds to mRNA encoding insulin-like growth factor II, which has been found to be overexpressed in HCC and is tumorigenic in transgenic animals. Immunohistochemical analysis of HCC liver showed that 33% (9 of 27) exhibited readily detectable staining of p62 protein in the cytoplasm of all malignant cells in cancer nodules, whereas it was undetectable in adjacent nonmalignant liver cells. In addition one of two patients with cholangiocarcinoma expressed p62 in malignant bile duct epithelial cells. p62 expression was also detected in scattered cells in cirrhotic nodules in contrast to uniform expression in all cells in HCC nodules. In HCC nodules, p62 mRNA was also detected by reverse transcriptase-polymerase chain reaction analysis. Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II.
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PMID:Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis. 1154 87

Patients with Wilson's disease (WD), Indian childhood cirrhosis (ICC), and idiopathic copper toxicosis (ICT) develop severe liver disease morphologically characterized by ballooning of hepatocytes, inflammation, cytoskeletal alterations, and Mallory body (MB) formation, finally leading to mostly micronodular cirrhosis. The pathogenesis of MBs in copper toxicosis is still unresolved. Immunohistochemical analysis of MBs in different types of copper intoxication revealed that keratin, p62, and ubiquitin are integral components. Thus MBs associated with copper intoxication resemble those present in alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). p62 is a multifunctional immediate early gene product that, on the one hand, is involved in stress-induced cell signaling (particularly that of oxidative stress) by acting as an adapter protein linking receptor-interacting protein (RIP) with the atypical protein kinase C. On the other hand, p62 binds with high affinity to polyubiquitin and ubiquitinated proteins. In conclusion, p62 accumulation in WD, ICC, and ICT and deposition in MBs indicates a central role of protein misfolding induced by oxidative stress in copper-induced liver toxicity. By sequestering potentially harmful misfolded ubiquitinated proteins as inert cytoplasmic inclusion bodies (e.g., as MBs), p62 may be a major player in an important cellular rescue mechanism in oxidative hepatocyte injury.
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PMID:Immunohistochemical analysis of Mallory bodies in Wilsonian and non-Wilsonian hepatic copper toxicosis. 1505

Strong interest exists about the biomolecular basis of the chronic liver diseases due to viral infections. It seems to be very interesting because of their evolutive potential. In this context the study of oncogenes and oncoproteins could be interesting as prognostic factors for chronic viral diseases of the liver. In this study the authors show the results obtained about EGF and p62 expression in 39 selected patients with cirrhosis and 3 different chronic viral hepatitis (persistent, lobular, and active).
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PMID:[Chronic viral diseases of the liver and oncoproteins externalization in hepatocytes]. 1672 87

Morphologic criteria of steatohepatitis are steatosis, ballooning of hepatocytes, often but not constantly associated with Mallory bodies, pericellular fibrosis and inflammation. Liver cirrhosis follows in about 20-50%. With respect to etiology an alcoholic and non-alcoholic type can be distinguished, the latter being a characteristic hepatic lesion associated with the metabolic syndrome (type II diabetes, insulin resistance, obesity, dyslipidemia). Ballooning of hepatocytes as well as Mallory body formation are associated with a disturbance of the keratin intermediate filament cytoskeleton. Mallory bodies are protein aggregates consisting of keratin (particularly keratin 8), p62, a stress-induced adapter protein involved in signal transduction pathways, heat shock proteins, and ubiquitin. Oxidative stress is involved in Mallory body formation. Major sources of oxidative stress in alcoholic and non-alcoholic steatohepatitis are the microsomal biotransformation system (cytochrome P-450) and the mitochondria, together with an impaired antioxidant defense system. Oxidative stress leads to misfolding/unfolding, abnormal phosphorylation of keratins and disturbance of keratin 8: keratin 18 ratio, and thus interferes with intermediate filament assembly. Moreover, impairment of cellular defense against abnormal proteins, i. e. chaperone action and proteasomal degradation, leads to the accumulation of abnormal aggregation--prone keratins (particularly keratin 8) which after ubiquitination associate with the stress-induced ubiquitin-binding protein p62 to form Mallory bodies. Thus, Mallory body formation resembles an "off-folding" protein response of the amyloid type. These pathogenetic principles of the human disease are supported by immunohistochemical and gene expression studies in experimental animals and by transfection experiments in tissue culture cells.
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PMID:[Alcoholic and non-alcoholic steatohepatitis]. 1803 83

Mallory bodies (MBs) and hyaline globules (HGs) are recognized as hepatocellular cytoplasmic inclusions in liver diseases. We reviewed 123 intrahepatic cholangiocarcinomas (ICCs) and encountered 16 cases (13.0%) in which cancer cells had MB-type inclusions and/or HG-type inclusions, both of which are positive for p62 and ubiquitin. The HG type was present in all 16 cases, and 5 cases contained the MB type. Of 16 patients, 12 had chronic liver disease that was related to alcoholic abuse in 4, hepatitis B surface antigen-positive in 3, and hepatitis C virus antibody-positive in 8. Viral infection and liver cirrhosis were more common in ICCs with p62+ inclusions (P = .0004 and P = .0199, respectively). Of 16 ICCs, 15 with hyaline inclusions had a peripheral tumor location (P = .0052). On ultrastructural examination, the MB type had an electron-dense fibrillar appearance, while the HG type appeared as rounded masses of granular materials. Our results suggest that intracytoplasmic hyaline bodies occasionally can be found in cholangiocarcinoma with chronic liver disease related to viral hepatitis or alcoholic intake.
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PMID:p62+ Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease. 2071 3

Hyperammonemia and sarcopenia (loss of skeletal muscle) are consistent abnormalities in cirrhosis and portosystemic shunting. We have shown that muscle ubiquitin-proteasome components are not increased with hyperammonemia despite sarcopenia. This suggests that an alternative mechanism of proteolysis contributes to sarcopenia in cirrhosis. We hypothesized that autophagy could be this alternative pathway since we observed increases in classic autophagy markers, increased LC3 lipidation, beclin-1 expression, and p62 degradation in immunoblots of skeletal muscle protein in cirrhotic patients. We observed similar changes in these autophagy markers in the portacaval anastamosis (PCA) rat model. To determine the mechanistic relationship between hyperammonemia and autophagy, we exposed murine C(2)C(12) myotubes to ammonium acetate. Significant increases in LC3 lipidation, beclin-1 expression, and p62 degradation occurred by 1 h, whereas autophagy gene expression (LC3, Atg5, Atg7, beclin-1) increased at 24 h. C(2)C(12) cells stably expressing GFP-LC3 or GFP-mCherry-LC3 constructs showed increased formation of mature autophagosomes supported by electron microscopic studies. Hyperammonemia also increased autophagic flux in mice, as quantified by an in vivo autophagometer. Because hyperammonemia induces nitration of proteins in astrocytes, we quantified global muscle protein nitration in cirrhotic patients, in the PCA rat, and in C(2)C(12) cells treated with ammonium acetate. Increased protein nitration was observed in all of these systems. Furthermore, colocalization of nitrated proteins with GFP-LC3-positive puncta in hyperammonemic C(2)C(12) cells suggested that autophagy is involved in degradation of nitrated proteins. These observations show that increased skeletal muscle autophagy in cirrhosis is mediated by hyperammonemia and may contribute to sarcopenia of cirrhosis.
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PMID:Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. 2289 79

Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved in inducing autophagy.
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PMID:Resveratrol Ameliorates Alcoholic Fatty Liver by Inducing Autophagy. 2762 19


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