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

It is well known that interferon-gamma (IFN-gamma; type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-gamma led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-gamma, IFN-alpha and IFN-beta (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C.
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PMID:Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2. Role of protein kinase C. 827 22

Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-beta twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P =.0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease.
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PMID:Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. 1117 57

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis and few therapeutic options. The aim of the study was to evaluate the potential of IFN regulatory factor-1 (IRF-1) for cytokine gene therapy of HCC using an IRF-1/human estrogen receptor fusion protein (IRF-1hER), which is reversibly activatable by beta-estradiol (E2). IRF-1hER stably expressing murine Hepa1-6 HCC cells (HepaIRF-1hER) were characterized by lowMHC 1, highCD54, and lack of MHC II, CD80, and CD86 expression. Activation of HepaIRF-1hER cells induced a highMHC I, lowMHC II, and highCD54 phenotype. Furthermore, they were characterized by IFN-beta secretion, decreased anchorage-independent growth in a soft agar assay, and diminished cell growth. Tumor growth in E2-treated syngeneic C57L/J mice, but not in E2-untreated mice, was suppressed. These E2-treated mice were protected against rechallenge with HepaIRF-1hER and wild-type Hepa1-6 tumors even in the absence of E2, suggesting induction of tumor specific immunity. In fact, significant CTL activity against Hepa1-6 tumors and the endogenously expressed HCC-specific self antigen alpha-fetoprotein was observed. Antitumoral effects, however, were only partially dependent on both CD4+ and CD8+ T cells. IRF-1 treatment of mice bearing HepaIRF-1hER tumors resulted in growth arrest of tumors, and a significant survival benefit was observed in comparison to E2-untreated mice. In conclusion, our data demonstrate that IRF-1 suppresses HCC growth through both a direct antitumor growth effect and enhanced immune cell recognition of the tumor and is a promising candidate for gene therapy of HCC.
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PMID:Growth suppression of the hepatocellular carcinoma cell line Hepa1-6 by an activatable interferon regulatory factor-1 in mice. 1128 38

In this study we examined the impact of hepatitis C virus (HCV) RNA replication on the innate antiviral response of the host cell. Replication of an HCV subgenomic replicon stimulated the activation of the interferon (IFN)-beta promoter and the production of IFN in human hepatoma cells. Using a variety of functional assays, we found that HCV RNA replication induced the activation and DNA-binding activity of NFkappaB and interferon regulatory factor (IRF)-1. In addition, microscopy experiments revealed a higher frequency of cells containing the nuclear-localized, active form of IRF-3 in HCV replicon cultures versus control cultures. Consistent with these observations, cells harboring the HCV replicon exhibited high basal level expression of a subset of IFN-stimulated antiviral genes. Our results indicate that HCV RNA replication can stimulate cellular antiviral programs that contribute to the assembly and activation of the IFN-beta enhanceosome complex and initiation of the antiviral state. Stable HCV RNA replication in the face of the host antiviral response suggests that HCV may encode one or more proteins capable of overcoming specific antiviral processes, thereby supporting persistent infection.
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PMID:Activation of the interferon-beta promoter during hepatitis C virus RNA replication. 1195 44

Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-alpha) and IFN-beta induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7, HuH7, PLC/PRF/5, HLE, and HLF). This synergism was only observed when cells were pretreated with the acyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with antitype 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2', 5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably because of a lack of IFNR and STAT1 up-regulation. In conclusion, these results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-beta.
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PMID:Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells. 1239 21

Mx proteins are members of a family of interferon-inducible genes that are expressed by cells in response to viral infection. They are important determinants of innate immunity against viral infection in vertebrates. We cloned the pufferfish ( Takifugu rubripes) Mx gene and sequenced 80 kb from the Mx locus. The Fugu Mx gene spans 3.4 kb from the transcription start site to the polyadenylation signal, and is made up of 12 exons and 11 introns. The protein sequence encoded by the Fugu Mx gene is 77%, 48%, and 51% identical to that of trout Mx1, chicken Mx, and mouse Mx1 genes, respectively. The Fugu Mx gene is expressed in a variety of tissues, with high expression detected in the heart, gill, kidney, intestine, and brain. Analysis of the 5'-flanking sequence of the gene showed the presence of two interferon-stimulated response elements (ISRE) at positions -51 to 38 and -97 to 85, relative to the transcription start site. The Fugu Mx promoter was inducible by human IFN-beta in the human hepatoma (Huh7) cells and by polyinosinic: polycytidilic acid in the top minnow hepatoma (PLHC-1) cells. Deletion analysis of the promoter showed that both ISREs contributed to inducibility. These results demonstrate that the molecular mechanisms involved in Mx gene regulation are conserved between fish and mammals.
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PMID:Molecular cloning of the pufferfish (Takifugu rubripes) Mx gene and functional characterization of its promoter. 1255 57

Thrombocytopenia is an important complication of interferon (IFN) therapy for chronic viral hepatitis. To study whether IFN interferes with hepatic thrombopoietin (TPO) synthesis, we used the human hepatoma cell line HepG2. Our results show that IFN-alpha, IFN-beta, or IFN-gamma did not impair TPO mRNA expression, as determined by quantitative RT-PCR, even when high IFN doses (up to 5000 U/ml) or long-term incubations (up to 14 days) were applied. Neither was the rate of secretion of immunoreactive TPO reduced on IFN treatment. These findings support the concept that IFNs primarily mediate effects on megakaryocytic cells and platelets rather than on TPO-producing hepatocytes.
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PMID:Thrombopoietin production in human hepatic cell cultures (HepG2) is resistant to IFN-alpha, IFN-beta, and IFN-gamma treatment. 1258 91

To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 +/- 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P << 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.
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PMID:A prospective comparison of the effect of interferon-alpha and interferon-beta treatment in patients with chronic hepatitis C on the incidence of hepatocellular carcinoma development. 1469 55

A 52-year-old male patient was admitted to our hospital for a further examination of liver tumor. He was positive for hepatitis C virus antibody. CT scanning revealed two hyper vascular tumors at the lateral segment of the liver and another one located at segment 8, an indication of hepatocellular carcinoma (HCC). Ascites were not detected and major serological findings were T-Bil 1.1 mg/dl, Alb 3.5 g/dl, ICG R15 12% and PT 88%. Lateral segmentectomy and a partial resection of the segment 8 were performed at the same time. An insertion of catheter in hepatic artery via gastroduodenal artery was carried out. Dehydropyrimidine dehydrogenase (DPD) activity of the tumor was 157 pmol/min/mg proteins. Recurrence was detected one year after the operation at segments 4 and 8. Arterial infusion chemotherapy using CDDP (10 mg), 5-FU (1,000 mg) and IFN-beta 3MU (continuous infusion for 5 days) was started two months later, and a complete response was achieved. The chemotherapy continued as long as severe adverse effects were not observed. However, two months after the tumor disappearance, the treatment discontinued due to occlusion of the infusion system. Recurrence occurred in two months at the same location where the previous tumor was. In conclusion, these results suggest that arterial chemotherapy using CDDP/5-FU/IFN-beta against HCC may be beneficial.
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PMID:[Successful hepatic arterial infusion therapy of CDDP/5-FU/IFN-beta3 for recurrent hepatocellular carcinoma]. 1555 89

Hepatitis C virus (HCV) is a major human pathogen that infects 170 million people. A hallmark of HCV is its ability to establish persistent infections reflecting the evasion of host immunity and interference with alpha/beta-IFN innate immune defenses. We demonstrate that disruption of retinoic acid-inducible gene I (RIG-I) signaling by the viral NS3/4A protease contributes to the ability of HCV to control innate antiviral defenses. RIG-I was essential for virus or HCV RNA-induced signaling to the IFN-beta promoter in human hepatoma cells. This signaling was disrupted by the protease activity of NS3/4A, which ablates RIG-I signaling of downstream IFN regulatory factor 3 and NF-kappaB activation, attenuating expression of host antiviral defense genes and interrupting an IFN amplification loop that otherwise suppresses HCV replication. Treatment of cells with an active site inhibitor of the NS3/4A protease relieved this suppression and restored intracellular antiviral defenses. Thus, NS3/4A control of RIG-I supports HCV persistence by preventing IFN regulatory factor 3 and NF-kappaB activation. Our results demonstrate that these processes are amenable to restoration through pharmacologic inhibition of viral protease function.
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PMID:Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. 1571 Aug 92


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