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)

Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 -/- MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.
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PMID:Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice. 1552 6

Hepatitis C virus (HCV) is the major causative viral agent of cirrhosis and hepatocarcinoma (HCC). HCV core protein affects cell homeostasis, playing an important role in viral pathogenesis of HCC. We investigate the effects of HCV core protein expression on cell growth in HCC cell lines. Cell cycle distribution analysis of HepG2 polyclonal core positive cells reveals a peculiar accumulation of cells in G2/M phase. Different pathways mediate G2/M arrest: such as p53 and double strand RNA protein kinase (PKR). Flow cytometry in p53-null cells demonstrates that p53 plays only a marginal role in inducing HCV core-dependent G2/M phase accumulation that seems to be significantly affected by the functional inactivation of PKR. HCC core positive cells are characterized by a significant PKR phosphorylation in Thr 446 residue, which leads deregulation of mitosis. Moreover, we observe that the overexpression of the viral protein induces an upregulation of PKR activity, which does not correlate with an increased eIF-2 phosphorylation. This uncommon behavior of PKR suggests that its activation by HCV core protein could involve alternative PKR-dependent pathways, implicated in core-dependent G2/M accumulation. The described biological effects of HCV core protein on cell cycle could be an additional viral mechanism for both HCV resistance to interferon (IFN) and HCC HCV-related pathogenesis.
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PMID:Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells. 1588 Apr 55

In the present study, the expression of P53 and MDM2 proteins were examined in specimens from a group of 20 patients (9 with primary hepatocellular carcinoma HCC and 11 with liver cirrhosis LC, linked to HBV infections as a major aetiologic factor) by immunohistochemistry. The immunostaining findings were correlated with P53 mutation analysis using PCR-SSCP, PCR-HDF and direct sequencing, and MDM2 amplification studies by differential PCR. P53 immunopositivity was found in 9 out of the 20 (45.0%) cases. Mutations of the P53 gene were detected in 5 (55%) tumors and 3 (27%) LC samples; 7 of these cases revealed P53 immunoreactivity. The mutations were base transitions at codons 175, 245 and 273; no changes were observed at codon 249, characteristic for aflatoxins action. MDM2 immunopositivity was revealed in 9 out of 20 (45.0%) specimens. MDM2 amplification occurred in 4 (44.4%) and 1 (9.1%) cases, HCC and LC specimens respectively; only in 2 tumors (10.0%), which exhibited MDM2 immunoreactivity. Overall, MDM2 positivity was not associated with MDM2 amplification in 7 out of the 20 studied samples (35.0%). Two HCC patients were found to have both gene abnormalities. Either the mutation rate of the P53 gene as well as the amplification level of the MDM2 gene was higher in HCC than in precancerous liver tissue stages. These results support the notion that besides P53 alterations, MDM2 gene deregulation seems to be an important event in hepatocarcinogenesis. Additionally, the mechanism of MDM2-mediated degradation of P53 protein, without involving stabilization and inactivation of P53 gene, should be considered for the understanding of all features of tumor progression processes.
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PMID:A comparative study of P53/MDM2 genes alterations and P53/MDM2 proteins immunoreactivity in liver cirrhosis and hepatocellular carcinoma. 1594 41

Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Common risk factors of human HCC include chronic hepatitis virus (HBV and HCV) infection, dietary aflatoxin B1 (AFB1) ingestion, chronic alcohol abuse, and cirrhosis associated with genetic liver diseases. Hepatocarcinogenesis is the result of interaction between hereditary and environmental factors. Inheritance determines individual susceptibility to cancer; environment determines which susceptible individuals express cancer. Studies of genetic and epigenetic mechanisms of hepatocarcinogenesis showed that HCC development is a complex polygene and multipathway process; the activation of proto-oncogenes and the inactivation of tumor suppressor genes induced by genetic and epigenetic alterations are core biological processes of hepatocarcinogenesis; RB1, p53, and Wnt pathways are commonly affected in HCCs of different etiologies, which may reflect common pathologic sequence of HCC: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and HCC of early stages. Hepatitis virus infection-associated HCCs have frequent alterations in RB1 pathway, including methylation of p16INK4a and RB1 genes and amplification of Cyclin D1. AFB1 exposure-associated HCCs have frequent alterations in p53 pathway; the G-->T mutation of p53 gene at codon 249 has been identified as a genetic hallmark of HCC caused by AFB1. Alcoholism-associated HCCs have frequent alterations in both RB1 and p53 pathways. The roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis had been discussed.
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PMID:[Molecular genetic and epigenetic mechanisms of hepatocarcinogenesis]. 1594 97

The clinical and morphological definition of hepatocellular carcinoma (HCC), dysplasia and adenoma suffers from a lack of biological understanding. This is especially important in the histomorphological diagnosis of nodular liver lesions in needle biopsies. Therefore, we constructed a liver tissue micro-array (TMA) and evaluated 48 HCCs, 46 dysplasias, 8 adenomas, 20 cirrhotic specimens and 28 normal liver samples derived from 68 patients. Protein (over)expression by tumor suppressor genes p16, p53 and Rb1 was assessed by immunohistochemistry, the proliferative capacity was examined by immunostaining of Ki67. Further, DNA ploidy status (hyperdiploidy) was measured by fluorescent in situ hybridization (FISH) with a chromosome 1-specific repetitive DNA probe. An abnormal chromosome 1 number, i.e. the percentage of hyperdiploid cells, was 11.0, 13.7, 16.1, 23.7 and 31.3 for normal liver samples, adenomas, cirrhosis, dysplasias and HCCs, respectively. A significant difference was found for HCC versus cirrhosis (P = 0.024) or adenoma (P = 0.033), a trend (borderline significance) was seen for dysplasia versus cirrhosis (P = 0.094). Immunohistochemical protein localisation of p53 and Rb1, as well as Ki67 indicating proliferation, was clearly higher in HCC than in cirrhosis or dysplasia (all P < 0.001). Proliferation was also higher in HCC than in adenoma (P = 0.025), whereas a trend (borderline significance) was observed for Rb1 overexpression (P = 0.063). These data suggest that in the liver cell dysplasia-carcinoma pathway, changes in ploidy are followed by increased proliferation and cell biological perturbations involving p53 and Rb1. Adenomas can be distinguished from carcinomas, but not from dysplasias, based on ploidy and proliferation characteristics.
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PMID:Cell biological evaluation of liver cell carcinoma, dysplasia and adenoma by tissue micro-array analysis. 1600 Feb 13

Hepatocellular carcinoma (HCC) from regions with high dietary exposure to aflatoxins and endemic for hepatitis B virus (HBV) often contain a specific mutation at codon 249 in TP53 (249(ser); AGG to AGT, Arg to Ser). This mutation is also detectable in circulating cell-free DNA from the plasma of HCC patients and healthy subjects in these regions. We have examined the joint effect of plasma 249(ser) and HBV infection in a case-control study design involving 348 control, 98 cirrhotic, and 186 HCC participants from The Gambia, West Africa, an area of high HCC incidence. The 249(ser) mutation was detected in 3.5% of controls, 15.3% of cirrhotics, and 39.8% of HCC cases (adjusted odds ratios (OR): 4.83, (95% confidence interval (CI): 1.71-13.7) for cirrhosis and 20.3 (8.19-50.0) for HCC). HBsAg positivity along with plasma 249(ser) was observed in 45/183 (24.6%) HCC cases compared to only one (0.3%) control. Risk for HCC was associated with markers of HBV alone (OR: 10.0, 95% CI: 5.16-19.6), 249(ser) alone (OR: 13.2, 95% CI: 4.99-35.0), and both markers present (OR: 399, 95% CI: 48.6-3270). These results suggest a multiplicative effect on HCC risk resulting from the mutational effect of aflatoxin on TP53, as monitored by detection of plasma 249(ser), with concomitant chronic infection with HBV.
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PMID:249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. 1600 11

The association of hepatitis B virus (HBV) infection and liver cancer is well documented in epidemiological study. Patients with chronic hepatitis B have increased risk of hepatocelluar carcinoma (HCC), in particular those with active liver disease and cirrhosis. The incidence of HCC increases with age and is more common among male patients. The introduction of universal HBV vaccination program for the newborn in endemic regions has started to show beneficial impact. Taiwan introduced this program two decades ago and the incidence of liver cancer among infants and young children have declined significantly. The carcinogenic events leading to HCC are under intense research. A number of hypotheses have been proposed. HBV is not directly hepatotoxic but its interaction with the host immune system creates opportunity for HBV DNA integration into the host genome. One of the main foci of research is the HBX-encoded X protein. Its integration and protein expression impose alteration in cell proliferation cycle and apoptosis process. Many other factors may be involved including viral-induced alterations in p53 and telemerase, HBV genotypes, co-infection with HCV or delta agents, patient's lifestyle such as smoking, alcohol excesses, and genetic factors of the host patient. The processes of necroinflammation, cell proliferation and fibrosis facilitate the initial carcinogenic development. HCC surveillance with tumor markers such as alpha-foetal protein, decarboxylated prothrombin, in conjunction with imaging techniques has identified early small HCC that is amenable to curative therapy. Viral load has been correlated with increase risk of HCC. The available anti-viral agents have demonstrated clinical benefit among those with maintained and sustained response. Interferon and lamivudine therapy have demonstrated reduction of HCC among responders. However, they only constitute a minority proportion of treated patients. The mainstay of prevention should lie in prevention of HBV infection and early effective therapy of chronic hepatitis B infection.
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PMID:HBV and liver cancer. 1610 76

To evaluate hepatic expression of the nuclear proliferative marker Ki-67 and the p53 oncoprotein in hepatitis B virus (HBV)/HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma (HCC). We studied needle liver biopsies from 107 patients with cirrhosis and no HCC (52 HBV, 55 HCV) who had been assessed for protocol studies, and 57 cirrhotic patients with HCC (40 HBV, 17 HCV). We evaluated small and large cell dysplastic changes along with the expression of Ki-67 and p53 by immunohistochemistry. The labelling index (LI) was defined as the proportion (%) of positive-stained nuclei of the 500 measured. Large and small cell dysplastic changes were observed in 12 and 9% of specimens respectively. Only small cell changes were associated with Ki-67 expression. Ki-67 LI was 5.50 +/- 5.7 in cirrhosis (13.90 +/- 3.84 in those with small cell dysplastic changes vs 4.64 +/- 4.98 in those without, P < 0.01), 10.2 +/- 5.95 in cirrhosis with HCC (P < 0.05) and 18.56 +/- 10 in HCC (P < 0.01). Neither the presence of small cell dysplastic changes nor the expression of Ki-67 was related to severity or aetiology of cirrhosis. Expression of p53 was observed in 30% of the non-tumorous and in 53% of the neoplastic tissue obtained from patients with HCC, with no differences between HCV and HBV. Ki-67 and p53 expression was associated with the tumour grade (P < 0.001). Our observations clearly demonstrate the association between the proliferation activity and the morphological changes in the cirrhotic liver from the non-dysplastic to dysplastic lesion to HCC. They also support the hypothesis that p53 alterations are a rather late event in carcinogenesis and related to HCC grade. And finally, they suggest that the final steps of hepatocarcinogenesis are common and independent of the aetiology of the chronic viral infection.
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PMID:Hepatic expression of the proliferative marker Ki-67 and p53 protein in HBV or HCV cirrhosis in relation to dysplastic liver cell changes and hepatocellular carcinoma. 1625 65

Growth arrest and DNA damage 45-alpha (GADD45-alpha) is a nuclear protein involved in maintenance of genomic stability, DNA repair, and suppression of cell growth through interaction with nuclear elements, including cyclin-dependent kinase inhibitor 1A (CDKN1A) and PCNA. In this study, GADD45-alpha expression was assessed in 28 cases of hepatocellular carcinoma (HCC) and matched cirrhosis tissues, and correlated with the presence of DNA-bound PCNA and CDKN1A as markers of DNA repair, as well as with clinicopathologic variables including histopathologic grade, tumor size, nodularity, viral status, alpha-fetoprotein serum levels, and p53 and Ki67 immunostaining. GADD45-alpha and CDKN1A messenger RNA (mRNA) were analyzed by reverse transcriptase-polymerase chain reaction. GADD45-alpha protein expression was evaluated by Western blot (WB) and enzyme-linked immunosorbent assays (ELISAs). PCNA and CDKN1A DNA-bound fractions were determined by WB. GADD45-alpha mRNA was down-regulated in 20 of 26 HCCs with respect to matched cirrhosis, but no correlation was found with the corresponding protein levels assessed by both WB and ELISA. GADD45-alpha and CDKN1A protein levels were related to each other both in cirrhotic and in neoplastic tissues, and a concordant up- or down-regulation was observed in HCCs with respect to cirrhosis. DNA-bound PCNA and CDKN1A were present in 5 HCCs and were associated with higher GADD45-alpha protein levels assessed by ELISA. No significant association was found in HCCs between GADD45-alpha protein expression and histopathologic grading, nodule size, focality, and proliferation, whereas a positive correlation was found with alpha-fetoprotein serum levels. In conclusion, GADD45-alpha mRNA was down-regulated with respect to matched cirrhosis in most HCCs; however, no correlation was found between mRNA and protein levels. GADD45-alpha protein levels were higher in HCCs with DNA-bound CDKN1A and PCNA, suggesting a possible role in DNA repair.
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PMID:GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. 1626 Feb 67

Hepatitis B virus (HBV) infections play an important role in the development of cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of HBV-related HCC, however, has not been fully described. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the pathogenesis of HCC. The high occurrence of anti-HBx antibody in the serum of HCC patients indicates that it could be a prognostic marker of HBV infection and HCC. HBx stimulates and influences signal transduction pathways within cells. HBx also binds to such protein targets as p53, proteasome subunits, and UV-damaged DNA binding proteins. It also interacts with the cyclic AMP-responsive element binding protein, ATF-2, NFkappaB, and basal transcription factors. HBx is primarily localized to the cytoplasm, where it interacts with and stimulates protein kinases, including protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. It is also found in the mitochondrion, where it influences the Bcl-2 family. This review examines the role of HBx in the life cycle of HBV as well as the various signal transduction pathways involved in the pathogenesis of HBV-induced hepatocarcinogenesis.
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PMID:Effects of hepatitis B virus X protein on the development of liver cancer. 1645 63


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