Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate Fas/FasL expression in hepatitis B virus-related chronic liver disease, liver biopsies from 44 such cases were studied immunohistochemically. FasL was detected in the infiltrating lymphocytes and both FasL and Fas were found in the hepatocytes. The Fas and FasL-positive cells were mostly found at the advancing edges of interphase hepatitis, and Fas/FasL expression was closely correlated with the inflammatory activity. Unexpectedly, FasL was also expressed in liver cirrhotic nodules, particularly in those with hepatocellular carcinoma with or without inflammation. These results suggest that the factors which induce hepatocyte transformation might also trigger FasL expression and promote FasL/Fas-mediated apoptosis.
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PMID:In situ investigation of Fas/FasL expression in chronic hepatitis B infection and related liver diseases. 931 Sep 28

The acute phase proteins alpha 1-acid glycoprotein (alpha 1-AGP) and alpha 1-antitrypsin (alpha 1-AT) were shown to inhibit, by a mechanism unidentified to date, the lethality induced by TNF both in normal mice and in mice sensitized with galactosamine. We found that both bovine alpha 1-AGP and human alpha 1-AT also inhibited specifically the induction of apoptosis of hepatocytes by TNF/ galactosamine in vivo. This inhibition is specific for TNF, since apoptosis induced by TNF and actinomycin D was also inhibited, while similar apoptosis of hepatocytes induced by anti-Fas remained unaffected. The observation that these acute phase proteins did not affect the induction by TNF of IL-6, nitric oxide, or serum amyloid P excludes a nonselective inhibition of the TNF-activated pathways. The protection conferred by alpha 1-AGP and alpha 1-AT is presumably indirect, since these proteins did not inhibit TNF/actinomycin D-induced apoptosis in the hepatoma cell lines HepG2 and BWTG3.
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PMID:Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice. 931 55

Fas antigen belongs to the tumor necrosis factor receptor family and is known to induce apoptosis. This protein is abundantly expressed in hepatocytes, especially in acute and chronic hepatitis. To elucidate the clinical significance of Fas in hepatocellular carcinoma (HCC), we investigated its expression in 50 HCC having various characteristics. Fas was comprehensively expressed in non-cancerous hepatocytes as well as bile ducts. It was moderately expressed in histiocytes in the stroma rather than in infiltrating lymphocytes. In HCC, Fas expression was significantly reduced when there was poor differentiation (p<0.001), portal tumor thrombus and extracapsular invasion (p<0.05) according to univariate analysis. Multivariate analysis revealed statistical significance between Fas expression and the degree of differentiation (p=0.0002). These results suggest that HCC, like non-cancerous hepatocytes, express Fas antigen, when they are well or moderately differentiated but lose this ability when they become poorly differentiated as the carcinoma advances.
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PMID:Fas antigen expression in hepatocellular carcinoma tissues. 945 89

We investigated the role of apoptosis in relation to proliferative activity in hepatocellular carcinoma (HCC) using in situ DNA nick end labeling (ISNEL) and immunostaining for the Ki-67 antigen in 35 patients with HCC. We also performed immunostaining for Fas and Fas ligand (Fas L) to determine the relationship between the Fas system and apoptosis. The ratio of the ISNEL labeling index (LI) to the Ki-67 LI was significantly lower in HCC than in surrounding nontumorous liver tissue (p<0.0001), suggesting that a decrease in apoptosis relative to cell proliferation is important in the pathogenesis of HCC. Fas and Fas L were expressed in both HCC and nontumorous tissue, but Fas and Fas L LIs were significantly lower in HCC (p<0.0001). Fas expression by cells near ISNEL-positive cells tended to be increased in nontumorous tissue in mirror-image sections, suggesting that apoptosis is related to Fas expression. However, this pattern was rarely observed in HCC. These findings indicate that the Fas system may not play a major role in apoptosis in HCC.
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PMID:The Fas system is not significantly involved in apoptosis in human hepatocellular carcinoma. 958 70

Fas (APO-1/CD95)-mediated apoptosis plays an important role in liver cell destruction in viral hepatitis. Using sandwich ELISA, we measured serum levels of soluble Fas (sFas) in patients with hepatocellular carcinoma (HCC) who were positive for hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibody. sFas levels were significantly higher in HCC patients (median 4.07 ng/ml; range 0.14-29.18 ng/ml) than levels in age-matched healthy donors (0.29 ng/ml; 0-4.90 ng/ ml) (P < 0.0001) and HBsAg or anti-HCV antibody-positive patients with liver cirrhosis (LC) (2.16 ng/ ml; 0.24-8.39 ng/ml) (P = 0.0015). An arbitrary cut-off level of 3.03 ng/ml (mean + 3 s.d. of controls) revealed the positive frequency of sFas in each group: 1.7% in healthy subjects, 25.9% in LC, and 59.0% in HCC (sensitivity 59.0% and specificity 74.1%). All HCC sera tested contained transmembrane-deleted sFas and some contained another sFas lacking the Fas C-terminal. The positive frequency of either sFas (59.0%) or alpha-fetoprotein (AFP) (57.4%) in HCC patients reached 77.0%. HCC patients with multiple tumour foci (7.53 ng/ml; 1.40-29.18 ng/ml) had significantly higher sFas levels than did patients with a solitary tumour (2.70 ng/ml; 0.14-19.0 ng/ml) (P = 0.003). In all of the sFas-positive patients with a solitary tumour, surgical removal of the tumour reduced sFas levels to the negative in the first post-op week. These findings suggest that sFas may be closely linked with HCC and may be a candidate for a clinical parameter for HCC.
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PMID:Elevated serum levels of soluble Fas/APO-1 (CD95) in patients with hepatocellular carcinoma. 964 77

The death receptor Fas transduces apoptotic death signaling mediated by caspases. In the present study, human hepatoma HepG2 cells showed the Fas-mediated apoptosis mediated by caspase, especially caspase 3, only in the presence of actinomycin D. Interestingly, cytosolic proteins extracted from intact HepG2 cells induced caspase 3 inactivation. Our results reveal that this inactivation was triggered by the direct inhibition of activated caspase 3 by IAP gene family ILP. In addition, a 53 kDa protein was co-immunoprecipitated with anti-human caspase 3 antibody from intact HepG2 cells. This protein was a complex-protein of procaspase 3 and the cell cycle regulator p21WAF1 (p21). P21 bound to only procaspase 3, but not to activated caspase 3. We also demonstrate that p21 protein-loaded HepG2 cells resist to Fas-mediated apoptosis even in the presence of actinomycin D. Here we report that caspase 3 inactivation for the resistance to Fas-mediated apoptosis is induced by a procaspase 3/p21 complex formation and direct inhibition of activated caspase 3 by ILP.
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PMID:Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. 974 72

The hepatitis B virus protein HBx is a promiscuous transactivator implicated in both cell growth and death and in the development of hepatocellular carcinoma. We recently reported that HBx can potentiate c-myc-induced liver oncogenesis in a transgenic model where low level expression of HBx induces no pathology. To assess if HBx could affect the hepatocyte turnover, we investigated the HBx-elicited apoptotic responses in transgenic livers and in primary hepatocyte cultures. Here we show that transgenic expression of HBx is associated with a twofold increase of spontaneous cell death in the mouse liver. The finding that apoptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not required to transduce the death signal. A direct, dose-dependent apoptotic function of HBx was demonstrated in transient transfections of liver-derived cell lines. We further show that stable expression of HBx at low, presumably physiological levels in primary hepatocytes, induced cellular susceptibility to diverse apoptotic insults, including growth factor deprivation, treatment with anti-Fas antibodies or doxorubicine and oxidative stress. HBx expression, but not p53 status profoundly affected the commitment of cells to die upon apoptotic stimuli. These data strengthen the notion that HBX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.
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PMID:p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro. 979 83

Lymph node (LN) cells of Fas-mutant mice lpr/lpr (lpr) and lpr(cg)/lpr(cg) (lpr(cg)) express an increased level of Fas ligand (FasL) (CD95L). We examined the antitumor potential of cell-bound FasL on these LN cells against Fas+ tumor cells. Fas+ F6b and Fas- N1d cells were produced from murine hepatoma MH134 (Fas-) by gene transfection. lpr and lpr(cg) LN cells inhibited growth of F6b but not N1d cells in vitro. Neither gld/gld lpr/lpr (gld/lpr) LN cells, which lack both FasL and Fas, nor wild-type LN cells showed growth-inhibitory activities against F6b and N1d cells. The effector cells and molecule were CD4-CD8- T cells and FasL, respectively. The tumor neutralization test and adoptive transfer demonstrated that lpr and lpr(cg), but not gld/lpr, LN cells retarded the growth of F6b cells. Although anti-Fas antibody and FasL cause severe liver failure, wild-type mice injected with lpr LN cells appeared clinically normal. Adoptive transfer of lpr LN cells to F6b-bearing mice exerted the same antitumor activity in wild-type and gld/lpr recipient mice, indicating the applicability of cell-bound FasL for Fas-mediated target therapy of cancer. These results suggest that antitumor activity was dependent on the Fas-FasL system and that lymphoid cells overexpressing FasL can be powerful antitumor effector cells against Fas+ tumor cells.
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PMID:Antitumor activity exhibited by Fas ligand (CD95L) overexpressed on lymphoid cells against Fas+ tumor cells. 982 39

The hepatitis B virus-encoded HBx protein coactivates transcription of viral and cellular genes, and it is believed to play an important role in hepatitis B virus-related liver cancer. HBx has been shown to alter the coordinated balance between proliferation and programmed cell death, being able to either induce or block apoptosis. Here, we demonstrate for the first time that the HBx is a potent caspase 3 inhibitor. Rat fibroblasts (REV2) and hepatoma cells (Hep) synthesizing the HBx protein were resistant to various apoptotic stimuli such as growth factor depletion, tumor necrosis factor alpha, or anti-Fas antibodies administration. In these cells, HBx prevented DNA fragmentation and cell death in the absence of de novo protein synthesis, with a similar efficiency as the competitive caspase 3 substrates inhibitors VAD-FMK and DEVD-FMK. Protein extracts obtained from the HBx positive cells contained a very low caspase activity, and addition of anti-HBx antibody restored the endogenous caspase activity. To obtain a functional map of the anti-caspase activity of HBx, various cell lines were established that synthesized either N-terminally or C-terminally truncated HBx molecules. These gene dissection experiments revealed that the regions required for the anti-caspase activity overlap with the two known transactivation domains of HBx.
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PMID:The hepatitis B virus HBx protein inhibits caspase 3 activity. 983 9

Chemotherapeutic drugs cause DNA damage and kill cancer cells mainly by apoptosis. p53 mediates apoptosis after DNA damage. To explore the pathway of p53-dependent cell death, we investigated if p53-dependent apoptosis after DNA damage is mediated by the CD95 (APO-1/Fas) receptor/ligand system. We investigated hepatoma, gastric cancer, colon cancer, and breast cancer cell lines upon treatment with different anticancer agents known to act via p53 accumulation. Cisplatin, mitomycin, methotrexate, mitoxantrone, doxorubicin, and bleomycin at concentrations present in the sera of patients during therapy led to an upregulation of both CD95 receptor and CD95 ligand. Induction of the CD95 ligand occurred in p53 wild-type (wt), p53 mutant (mt), and p53 deficient (p53(-/-)) cell lines and at wt and mt conformation of temperature-sensitive p53 mutants. In contrast, upregulation of the CD95 receptor was observed only in cells with wt p53, not in cells with mt or without any p53. Restitution of inducible wt p53 function restored the ability of p53(-/-) Hep3B cells to upregulate the CD95 receptor in response to anticancer drugs. This rendered the cells sensitive to CD95-mediated apoptosis. In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, whereas mt p53 failed to induce apoptosis via activation of the CD95 gene. These observations provide a mechanistic explanation for the ability of p53 to contribute to tumor progression and to resistance of cancer cells to chemotherapy.
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PMID:p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. 984 17


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