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)

We combined the specificity of tumor-specific antibody with the chemokine function of interferon-gamma inducible protein 10 (IP-10) to recruit immune effector cells in the vicinity of tumor cells. A novel fusion protein of IP10-scFv was constructed by fusing mouse IP-10 to V(H) region of single-chain Fv fragment (scFv) against acidic isoferritin (AIF), and expressed in NS0 murine myeloma cells. The IP10-scFv fusion protein was shown to maintain the specificity of the antiAIF scFv with similar affinity constant, and bind to the human hepatocarcinoma SMMC 7721 cells secreting AIF as well as the activated mouse T lymphocytes expressing CXCR3 receptor. Furthermore, the IP10-scFv protein either in solution or bound on the surface of SMMC 7721 cells induced significant chemotaxis of mouse T cells in vitro. The results indicate that the IP10-scFv fusion protein possesses both bioactivities of the tumor-specific antibody and IP-10 chemokine, suggesting its possibility to induce an enhanced immune response against the residual tumor cells in vivo.
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PMID:A novel fusion protein of IP10-scFv retains antibody specificity and chemokine function. 1521 58

Chronic hepatitis B virus infection is a serious problem because of its worldwide distribution and possible adverse chronic sequelae, such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is a dynamic state of interactions between the virus, hepatocyte and host immune response. Interferon-alpha and direct antiviral agents, such as lamivudine (Epivir, GlaxoSmithKline), are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory. Thymalfasin (thymosin alpha1; Talpha1, Zadaxintrade mark, SciClone Pharmaceuticals, Inc.) is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that Talpha1 can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-gamma and interleukin-2, and activate natural killer cell-mediated cytotoxicity. Seven randomized controlled studies on Talpha1 monotherapy in patients with chronic hepatitis B showed that 6 months treatment with Talpha1 (1.6 mg twice-weekly) resulted in a significantly higher sustained response rate than untreated controls. The benefits of Talpha1 therapy is usually not immediately apparent during therapy. There is a trend for complete virological response to increase or accumulate gradually after the end of thymosin therapy. The results of Talpha1 and interferon combination therapy in two open-label trials were also promising. In terms of the mechanisms of action, a combination of Talpha1 and nucleoside or nucleotide analogs is a logical approach in the control of chronic HBV infection and a randomized control study is ongoing.
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PMID:Thymalfasin for the treatment of chronic hepatitis B. 1548 67

We recently cloned a new member of cancer/testis antigen named HCA587, which was highly expressed in human hepatocellular carcinoma (HCC) tissues. To investigate it as a potential tumour-specific target for immunotherapy, the immunogenicity of this protein, especially the ability to induce specific cellular immune responses, was evaluated in the present study. As dendritic cells (DC) are the most potent antigen-presenting cells, DC-based vaccination has recently shown marked promise for the treatment of human malignancies by immunological intervention. Here, we demonstrate that autologous DC loaded with HCA587 protein could induce specific T-cell responses in healthy individuals by in vitro stimulations. Enzyme-linked immunospot analysis for interferon-gamma (IFN-gamma) secretion demonstrated HCA587-specific CD8(+) T cells in the antigen-stimulated peripheral blood lymphocytes, and the analysis of CD4(+) T cells by proliferation assay also showed antigen-specific reactivities in normal donors. Two-colour flow cytometric analysis of surface markers and intracellular cytokine expression demonstrated that HCA587-specific cytotoxic T lymphocytes exhibited a heterogeneous CD8(+)/CD56(+) expression, and a striking T-helper 1 cytokine bias (IFN-gamma(high)/IL-4(low)) was observed for both CD4(+) and CD8(+) HCA587-specific lymphocyte populations. We conclude that HCA587 is a potent immunogen that can induce CD4(+) and CD8(+) T-cell-mediated specific immune responses, and these findings propose HCA587 as a good candidate for the development of a therapeutic protein-based DC tumour vaccine for the treatment of HCC patients.
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PMID:Elicitation of both CD4 and CD8 T-cell-mediated specific immune responses to HCA587 protein by autologous dendritic cells. 1554 Oct 44

Nur77, an orphan nuclear receptor, has been implicated in apoptosis of a variety of cell types, including hepatocytes. The small heterodimer partner (SHP) binds and inhibits the function of many nuclear receptors. Here, we investigated cross-talk between Nur77 and SHP during anti-Fas antibody (CH11)-mediated apoptosis of hepatic cells. Expression of SHP decreased, whereas antisense SHP enhanced, the transcriptional activity of Nur77 in HepG2 cells. SHP and Nur77 were physically associated in vivo and colocalized in the nucleus. SHP decreased the transactivation function of the N-terminal domain of Nur77 that recruits coactivators. Nur77 and SHP competitively bound to cAMP response element-binding protein-binding protein and the expression of coactivators, such as cAMP response element-binding protein-binding protein and activating signal cointegrator-2, recovered the decreased function of Nur77 caused by SHP. Finally, SHP was differentially expressed in hepatoma cell lines in that it was not detected in the interferon-gamma (IFNgamma)/CH11-sensitive SNU354, whereas it was significantly expressed in the IFNgamma/CH11-resistant HepG2. Interestingly, a stable SNU354 cell line that expressed SHP became resistant to the IFNgamma/CH11-induced apoptosis. Together, our results suggest that SHP plays a key role in the regulation of Nur77 activation and thereby in Nur77-mediated apoptosis in the liver.
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PMID:Negative cross-talk between Nur77 and small heterodimer partner and its role in apoptotic cell death of hepatoma cells. 1562 37

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

Although the proinflammatory cytokine interferon-gamma (IFN-gamma) has been generally thought to enhance antitumor immune responses and be involved in antitumor mechanisms of many other immunotherapy molecules, it has also been reported that IFN-gamma could promote tumor immune evasion. In this report, by using an ideal mouse model that expresses IFN-gamma locally in muscle, we demonstrate that sustained low-level expression of IFN-gamma promotes the development of several types of tumor including H22 hepatoma, MA782/5S mammary adenocarcinoma and B16 melanoma. However, transitory expression of IFN-gamma does not have such an effect. On the other hand, sustained high-level expression of IFN-gamma mediates significant antitumor effect on H22 hepatoma. Low level of IFN-gamma upregulates expression of PD-L1, PD-L2, CTLA-4 and Foxp3, which may partly account for the tumor immune evasion promoted by IFN-gamma. Furthermore, blockade of PD-L inhibits IFN-gamma's tumor-promoting effect. Our findings provide a mechanistic link between chronic inflammation and cancer and would have potential implications for cancer prevention and also for the design of cytokine-based cancer immunotherapy.
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PMID:Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy. 1577 83

Natural killer (NK) cells are specialized lymphocytes that provide a first line of defense through their ability to kill pathogen-infected cells and transformed cells. The function of NK cells is regulated by a fine balance of inhibitory and activating signals, which are mediated by a diverse array of cell-surface receptors. We recently found that expression of the inhibitory receptor CD94/NKG2A is up-regulated on NK cells in patients with chronic hepatitis C. HLA-E, a ligand for NKG2A, was expressed in all human hepatoma cell lines tested as well as in nontransformed hepatocytes, but not in K562 cells, a classic NK-sensitive target. NK cells isolated from patients with chronic hepatitis C (HCV-NK) were less capable of killing hepatoma cells and of producing interferon-gamma in response to hepatoma cells than those from healthy donors, whereas there was no significant difference in NK responsiveness toward K562 cells. Of note is the finding that maturation and activation of monocyte-derived dendritic cells were negatively modulated in the presence of HCV-NK and hepatoma cells, which were restored by the addition of anti-NKG2A antibody during the coculture of HCV-NK and hepatoma cells. Research revealed that dendritic cells recognize danger signals from microorganisms by monitoring pathogen-associated molecular patterns via Toll-like receptors. Our findings have shed light on NK receptors as an important interface that transmits danger signals from abnormal cells to immune systems. Aberrant expression of CD94/NKG2A should have negative impact on innate resistance and subsequent adaptive immunity toward HCV-infected or transformed cells in chronic hepatitis C.
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PMID:Natural killer cells in hepatitis C virus infection: from innate immunity to adaptive immunity. 1623 66

Viral modification of dendritic cells (DCs) may deliver a "danger signal" critical to the hypo-reactive DCs in cancer patients. Using three highly differentially expressed hepatoma tumor-associated antigens (TAAs): stem cell antigen-2 (Sca-2), glycoprotein 38 (GP38) and cellular retinoic acid binding protein 1 (RABP1), we explored the therapeutic potential of the DCs modified with lentiviral vectors (LVs). Preventive and therapeutic injection of the LV-TAA-DC vaccine into tumor-bearing mice elicited a strong anti-tumor response and extended survival, which was associated with tumor-specific interferon-gamma and cytotoxic T cell responses. In vivo elimination of the LV-TAA-DCs by a co-expressed thymidine kinase suicide gene abrogated the therapeutic effect. The modification of DCs with LVs encoding multiple TAAs offers a great opportunity in cancer immunotherapy.
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PMID:An effective cancer vaccine modality: lentiviral modification of dendritic cells expressing multiple cancer-specific antigens. 1653 Mar 3

Hepatitis C virus (HCV) infection correlates with human immune disorders characterized by abnormal activation and proliferation of lymphocytes. Interaction of HCV major envelope protein E2 with susceptible cells occurs at an early stage of the viral infection. HCV tropism for susceptible cells may elicit cellular signaling events implicated in the viral pathogenicity, and E2 protein is known to be responsible for the tropism. We documented previously that HCV E2 protein was capable of activating extracellular signal-regulated kinase (ERK) in human hepatoma Huh-7 cells. Here, ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways were investigated in human T lymphoma cell line Molt-4 in response to HCV E2 protein. Binding of HCV E2 protein to Molt-4 cells was detectable, and such interaction was a determinant for recognition and delivery of the E2 signal to intracellular pathways. Activation of ERK and p38 MAPK was specifically induced following the HCV E2-cell interaction. CD81 and low-density lipoprotein receptor (LDLR), proposed cellular receptors for HCV, were expressed naturally on Molt-4 cells. CD81 and LDLR were shown to mediate HCV E2-induced activation of ERK and p38 MAPK. In CD81-deficient U937 cells, levels of ERK and p38 MAPK activation and cell proliferation induced by HCV E2 protein were lower than those in Molt-4 cells. Furthermore, cell proliferation and secretion of interferon-gamma and interleukin-10 by Molt-4 cells were promoted by HCV E2 protein. Therefore, ERK and p38 MAPK signaling pathways were up-regulated by HCV E2 protein without synergetic stimulation, which was accompanied by alterations of cell behavior.
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PMID:Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line. 1679 13

Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.
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PMID:Increased frequencies of CD8+ T lymphocytes recognizing wild-type p53-derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma. 1699 81


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