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)

The hepatitis C virus (HCV) causes chronic hepatitis, which often results in liver cirrhosis and hepatocellular carcinoma. We have previously shown that HCV nonstructural proteins induce activation of STAT-3 via oxidative stress and Ca2+ signaling (G. Gong, G. Waris, R. Tanveer, and A. Siddiqui, Proc. Natl. Acad. Sci. USA 98:9599-9604, 2001). In this study, we focus on the signaling pathway leading to STAT-3 activation in response to oxidative stress induced by HCV translation and replication activities. Here, we demonstrate the constitutive activation of STAT-3 in HCV replicon-expressing cells. The HCV-induced STAT-3 activation was inhibited in the presence of antioxidant (pyrrolidine dithiocarbamate) and Ca2+ chelators (BAPTA-AM and TMB-8). Previous studies have shown that maximum STAT-3 transactivation requires Ser727 phosphorylation in addition to tyrosine phosphorylation. Using a series of inhibitors and dominant negative mutants, we show that HCV-induced activation of STAT-3 is mediated by oxidative stress and influenced by the activation of cellular kinases, including p38 mitogen-activated protein kinase, JNK, JAK-2, and Src. Our results also suggest a potential role of STAT-3 in HCV RNA replication. We also observed the constitutive activation of STAT-3 in the liver biopsy of an HCV-infected patient. These studies provide an insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with the viral infection.
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PMID:Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress: role of STAT-3 in HCV replication. 3293 69

NKT cells are a regulatory subset of T lymphocytes with immune modulatory effects and an important role in anti-tumor immunity. The feasibility of "ex-vivo education" of NKT cells has recently been demonstrated. To evaluate the anti-tumor effect of ex-vivo immune-modulated NKT lymphocytes in a murine model of hepatocellular carcinoma. Athymic Balb/C mice were sublethally irradiated and transplanted with human Hep3B HCC. NKT cells prepared from immunocompetent Balb/C mice were pulsed ex vivo with HCC-derived antigens (Group A), Hep3B cells (group B) or BSA (group C), and adoptively transferred into HCC harboring mice (1 x 0(6) NKT cells per mouse). Group D mice did not undergo NKT cell transplantation. Group E mice were transplanted with 1 x 10(6) NKT cells from HBV-immunized donors. Mice were followed for tumor size and weight. To determine the mechanism of the anti-tumor effect, intrasplenic lymphocyte populations were analyzed by FACS for NKT, CD4+ and CD8+ lymphocyte subpopulations; STAT 1, 4 and 6 expression in splenocytes was assessed by Western blot, and serum cytokine levels were measured by ELISA. Adoptive transfer of NKT cells pulsed with HCC-derived antigens (group A) and NKT cells from immunized donors (group E) resulted in complete disappearance of tumors within 4 weeks and attenuated weight loss (6.5% and 7% in groups A and E, respectively). In contrast, mice in groups B, C, and D developed large, necrotic tumors and severe weight loss (21%, 17% and 23% weight loss in groups B, C, and D, respectively). NKT/CD4 and CD8/CD4 ratios were significantly increased in groups A and E (12.3 and 17.6 in groups A and D, respectively, compared to 6.4, 4.8 and 5.6 in groups B, C and D, respectively, for the NKT/CD4 ratio; 41 and 19.8 in groups A and E, respectively, compared to 6.5, 11.8 and 3.2 in groups B, C, and D, respectively, for the CD8/CD4 ratio). Expression of the transcription factor STAT4 was evident in group A, but not in groups B-D. Serum IFNgamma, IL12 and IL4 levels were increased in groups A and E. Adoptive transfer of NKT lymphocytes exposed ex vivo by HCC-derived antigens loaded on dendritic cells and NKT cells from immunized donors led to suppression of HCC in mice. NKT-mediated anti-tumor activity was associated increased NKT and CD8+ T lymphocyte numbers, increased expression of STAT4, a marker for IL-12 activity and elevated serum levels of the proinflammatory cytokines IFNgamma and IL12, and of IL4. Ex-vivo modulation of NKT lymphocytes holds promise as a novel mode of immune therapy for HCC.
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PMID:Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes. 1568 66

Interferon-alpha (IFN-alpha) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK-STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN-alpha is demonstrated here. The transcriptional levels of SOCS-1 and -3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription-polymerase chain reaction. We established stable transfectants of SOCS-1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS-1 on the phosphorylation of IFN-alpha-induced STAT-1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS-1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS-1, but not SOCS-3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN-alpha-induced STAT-1 phosphorylation and the expression of antiviral genes were inhibited in SOCS-1-transfected cells. Patients showing high SOCS-1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS-1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS-1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS-1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.
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PMID:Enhanced expression of suppressor of cytokine signalling-1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy. 1572 May 27

Generation of reactive oxygen species (ROS) with the accumulation of oxidative damage has been implicated in neurodegenerative disease and in the degradation of nervous system function with age. Here we report that ROS inhibit the activity of ciliary neurotrophic factor (CNTF) in nerve cells. Treatment with hydrogen peroxide (H(2)O(2)) as a generator of ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells, and SH-SY5Y and BE(2)-C human neuroblastoma cells. H(2)O(2) treatment of non-neuronal cells, chick skeletal muscle and HepG2 hepatoma cells, did not inhibit Jak/STAT signaling. The H(2)O(2) block of CNTF activity was seen at concentrations as low as 0.1 mm and within 15 min, and was reversible upon removal of H(2)O(2) from the medium. Also, two other mediators of oxidative stress, nitric oxide and rotenone, inhibited CNTF signaling. Treatment of neurons with H(2)O(2) and rotenone also inhibited interferon-gamma-mediated activation of Jak/STAT1. Depleting the intracellular stores of reduced glutathione by treatment of BE(2)-C cells with nitrofurantoin inhibited CNTF activity, whereas addition of reduced glutathione protected cells from the effects of H(2)O(2). These results suggest that disruption of neurotrophic factor signaling by mediators of oxidative stress may contribute to the neuronal damage observed in neurodegenerative diseases and significantly affect the utility of CNTF-like factors as therapeutic agents in preventing nerve cell death.
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PMID:Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons. 1574 69

We have studied the effects of heavy metals (Hg2+, Cu2+, Cd2+) on growth hormone (GH) activation of tyrosine kinase and Ca2+ signaling in the trout (Oncorhynchus mykiss) hepatoma cell line RTH-149. Molecular cloning techniques using primer designed on Oncorhynchus spp. growth hormone receptor (GHR) genes allowed to isolate a highly homologous cDNA fragment from RTH-149 mRNA. Thereafter, cells were analysed by Western blotting or, alternatively, with Ca2+ imaging using fura-2/AM. Exposure of cells to ovine GH alone produced a stimulation of the JAK2/STAT5 pathway and intracellular free Ca2+ variations similar to what has been observed in mammalian models. Cell pre-exposure to Cu2+, Hg2+ or Cd2+ affected cell response to GH by enhancing (Cu2+) or inhibiting (Cd2+) the phosphorylation of JAK2 and STAT5. Heavy metals induced the activation of the MAP kinase p38, and pre-exposure to Hg2+ or Cu2+ followed by GH enhanced the effect of metal alone. Image analysis of fura2-loaded cells indicated that pre-treatment with Hg2+ prior to GH produced a considerable increase of the [Ca2+]i variation produced by either element, while using Cu2+ or Cd2+ the result was similar but much weaker. Data suggest that heavy metals interfere with GH as follows: Hg2+ is nearly ineffective on JAK/STAT and strongly synergistic on Ca2+ signaling; Cu2+ is activatory on JAK/STAT and slightly activatory on Ca2+; Cd2+ is strongly inhibitory on JAK/STAT and slightly activatory on Ca2+; heavy metals could partially activate STAT via p38 independently from GH interaction.
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PMID:Heavy metal interference with growth hormone signalling in trout hepatoma cells RTH-149. 1595 44

The potential anti-proliferation effect of interferon-alpha (IFN-alpha) against hepatocellular carcinoma (HCC) and its growth inhibitory mechanisms remain unclear. We examined four human HCC cell lines and every cell line had the anti-proliferative effect of IFN-alpha. The PLC/PRF/5 cell line, which expressed the IFN receptor most abundantly, responded most effectively to IFN-alpha stimulation. Here, we delineate the anti-proliferative effect of IFN-alpha via the MAPK pathway in human HCC cell lines. IFN-alpha retarded G1/S transition with no evidence of apoptosis and inhibited cell proliferation. IFN-alpha diminished the phosphorylation of both extracellular signal-regulated kinase (ERK) and mitogen-activated ERK-regulating kinase (MEK), but not Raf, within 5 min. Knockdown of signal transducers of activation and transcription1 (STAT1) or Janus kinase1 (JAK1) suppressed the reduction of phosphorylation both of ERK and MEK and diminished the growth inhibition by IFN-alpha. These results suggest that IFN-alpha induces anti-proliferative signaling via the JAK/STAT pathway downstream of IFN-alpha receptors and may reduce the growth stimulation signaling by cross-talk with the MEK/ERK pathway without IFN-alpha-induced transcription.
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PMID:Rapid inhibition of MAPK signaling and anti-proliferation effect via JAK/STAT signaling by interferon-alpha in hepatocellular carcinoma cell lines. 1605 12

Interferon alpha (IFN-alpha)-based therapy is the currently approved treatment for chronic hepatitis C viral infection. The sustained antiviral response rate is approximately 50% for genotype-1 infection. The major challenge to the HCV community is to improve antiviral efficacy and to reduce the side effects typically seen in IFNalpha-based therapy. One of the strategies is to identify new interferons, which may have better efficacy and less undesirable side effects. In this report, we examined the role of IL-28A (IFN lambda2), a novel type I IFN, in suppression of human hepatitis C viral RNA replication. We have cloned both the human genomic DNA and cDNA of IL-28A, and evaluated their biological activity using HCV RNA replicon cell culture system. The results show that IL-28A effectively inhibits HCV subgenomic RNA replication in a dose-dependent manner. Treatment of human hepatoma cells with IL-28A activates the JAK-STAT signaling pathway and induces the expression of some interferon-stimulated genes (ISGs), such as 6-16 and 1-8U. We also demonstrate that IL-28A induces expression of HLA class I antigens in human hepatoma cells. Moreover, IL-28A appears to specifically suppress HCV IRES-mediated translation. Although IL-28A receptor shares one subunit with the IL-10 receptor, IL-10 treatment has no detectable effect on IL-28A-induced antiviral activity. Interestingly, IL-28A can synergistically enhance IFNalpha antiviral efficacy. Our results suggest that IL-28A antiviral activity is associated with the activation of the JAK-STAT signaling pathway and expression of ISGs. The effectiveness of IL-28A antiviral activity and its synergistic effect on IFN-alpha indicate that IL-28A may be potentially used to treat HCV chronic infection.
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PMID:Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication. 1614 71

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

Growth hormone (GH) is secreted in a pulsatile pattern to promote body growth and metabolism. GH exerts its function by activating several signaling pathways, including JAK2/STAT and MEK/ERK. ERK1/2 activation by GH plays important roles in gene expression, cell proliferation, and growth. We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure, a second GH exposure induces STAT5 phosphorylation but not ERK1/2 phosphorylation (Ji, S., Frank, S. J., and Messina, J. L. (2002) J. Biol. Chem. 277, 28384-28393). In this study the mechanisms underlying GH-induced homologous desensitization were investigated. A second GH exposure activated the signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. This correlated with recovery of GH receptor levels, but was insufficient for GH-induced phosphorylation of MEK1/2 and ERK1/2. Insulin restored the ability of a second GH exposure to induce phosphorylation of MEK1/2 and ERK1/2 without altering GH receptor levels or GH-induced phosphorylation/activation of JAK2 and Raf-1. GH and insulin synergized in promoting cell proliferation. Further investigation suggested that insulin increased the amount of MEK bound to KSR (kinase suppressor of Ras) and restored GH-induced tyrosine phosphorylation of KSR. Previous GH exposure also induced desensitization of STAT1 and STAT3 phosphorylation, but this desensitization was not reversed by insulin. Thus, insulin-regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal, physiologic pulse of GH.
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PMID:Insulin reverses growth hormone-induced homologous desensitization. 1671 97

Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of hepatocellular carcinomas. Recent studies of EGFR inhibitors to treat hepatocellular carcinoma have been encouraging and better understanding of EGFR signaling may lead to more effective strategies for inhibiting this key pathway. The EGFR can be phosphorylated at different tyrosine sites, leading to subsequent activation of different pathways. Cell line and animal studies have shown that MAPK and STAT-3 are important mediators of the EGFR signal in liver cells. However, little is known about EGFR phosphorylation and subsequent signaling in primary hepatocellular carcinoma. We investigated the site of EGFR phosphorylation by Western blot in 18 hepatocellular carcinomas. Fourteen of 18 hepatocellular carcinomas had detectable EGFR by Western blotting and 13 of 14 showed phosphorylation at tyrosine 845. In contrast, no EGFR phosphorylation was detected at tyrosine 998, tyrosine 1045, or tyrosine 1068, which signal through other pathways including STAT-3 and MAPK. These findings were further explored by examination of EGFR expression and signaling pathway activation in tissue arrays comprised of 73 hepatocellular carcinomas using antibodies that recognize phosphorylated (or activated) proteins. Tissue array studies also found no correlation between EGFR expression (29% of cases) and STAT-3 nuclear positivity (16%), AKT (4%), MAPK (3%), or STAT-5 (3%) positivity, all P>0.05. EGFR expression was correlated with hepatitis B infection, but not with tumor size, nuclear grade, or proliferative rate. We conclude that EGFR is phosphorylated at tyrosine 845 in most hepatocellular carcinomas and that EGFR expression by immunohistochemistry does not correlate well with STAT-3, STAT-5, MAPK, or AKT immunostaining.
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PMID:EGFR is phosphorylated at Ty845 in hepatocellular carcinoma. 1693 1


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