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 blood level of erythropoietin (Epo) is often anomalously low in anemic patients with inflammatory or malignant diseases. Therefore, we studied effects of pure recombinant immunomodulatory peptides on Epo formation in cultures of the human hepatoma cell line, HepG2. Interleukin (IL)-1 beta, IL-1 alpha, and tumor necrosis factor alpha lowered Epo production with half-maximal inhibition at 2, 5, and 20 U/ml, respectively. IL-6, transforming growth factor beta 2 and interferon gamma did not inhibit. Furthermore, IL-1 beta (10 U/ml) proved to block Epo formation in isolated serum-free perfused rat kidneys. Proposedly, monokines play a role in the pathogenesis of Epo deficiency in various diseases.
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PMID:Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. 131 Jan 33

Intercellular adhesion molecule 1 (ICAM-1), a counter-receptor for lymphocyte function-associated antigen 1 on T cells, is critically important to a wide variety of adhesion-dependent leukocyte functions, including antigen presentation and target cell lysis. ICAM-1 expression by hepatocytes is increased in areas of inflammation and necrosis during chronic hepatitis B. Whether induction of ICAM-1 is due to the effect of inflammatory cytokines or involves a direct effect of the hepatitis B virus (HBV) remains unknown. In the present study, transfection of the HBV genome into human hepatoma cell lines resulted in enhanced expression of ICAM-1 protein and RNA in the absence of inflammation. Results of subgenomic transfections indicated that the HBV X protein (pX) induced ICAM-1 expression. Nuclear run-on assays showed that pX induced the ICAM-1 gene by increasing its rate of transcription. Although both pX and interferon gamma induced transcription of ICAM-1, addition of interferon gamma to cells expressing pX did not show an additive or synergistic effect. These results indicate that pX can directly regulate expression of ICAM-1 and may participate in the immunopathogenesis of HBV infection.
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PMID:Up-regulation of intercellular adhesion molecule 1 transcription by hepatitis B virus X protein. 136 Jun 68

C1 inhibitor (C1INH), the major plasma inhibitor of activated C1, kallikrein, and activated Hageman factor, may be an important factor in limiting inflammatory injury mediated by the complement and contact systems. C1INH is thought to be synthesized primarily in the liver; however, the regulators of hepatic C1 inhibitor synthesis are completely unknown. In this report, we analyze the regulation of C1INH synthesis by hepatocyte stimulating factors in human hepatoma cell lines and primary hepatocytes. Interleukin-6 and interferon gamma increase C1INH production in both hepatoma cells and hepatocytes. These cytokines stimulate de novo synthesis of functional C1INH, acting at a pretranslational level as assessed by Northern blotting. The stimulatory effects of interleukin-6 and interferon gamma on C1INH synthesis are separate and are differentially modulated by interleukin-1. These results establish that hepatic C1INH synthesis is regulated by hepatocyte stimulating factors and reveal novel interactions between these factors.
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PMID:Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. 169 34

Novel immunotherapeutic strategies for combating colon cancer are also being explored in pancreatic, hepatic, and esophageal cancers. Preliminary clinical trials in patients with pancreatic cancer suggest a therapeutic role for anti-idiotypic antibodies against tumor-specific monoclonal antibodies (MoAbs)--eg, CO17-1A, BW 494/32--but not for MoAbs when used alone. Adding low doses of interferon gamma to CO17-1A enhances in vitro antibody-dependent cellular cytotoxicity against pancreatic tumor cells; CO17-1A plus a regimen of 5-FU/doxorubicin/mitomycin has resulted in beneficial therapeutic effect. Treatments with immunotoxins, radiolabeled MoAbs, and adoptive immunotherapy are still being tested preclinically. In 105 patients with unresectable hepatocellular cancer, a 7% complete and 41% partial regression rate with 131I-labeled antiferritin has been reported. In several patients, radiolabeled antiferritin caused sufficient shrinkage of lesions to permit curative resection. Pretreatment with low-dose doxorubicin may improve the efficacy of low-dose radiolabeled antiferritin antibody therapy. Chemoembolization of primary hepatocellular carcinoma, based on the concept of regional therapy for metastatic colorectal cancer, has shown considerable palliative and survival benefit in patients with unresectable disease. Although adoptive immunotherapy has been used to treat hepatocellular carcinoma, the results have been disappointing. The development of immunotherapeutic approaches to esophageal cancer is less advanced than that for other gastrointestinal malignancies. Paralleling the successful use of 5-FU/interferon alfa-2a in colon cancer are two phase II studies that have evaluated this combination in patients with locally advanced esophageal cancer. The objective response rate (27%) was encouraging.
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PMID:Implications of current therapeutic approaches in colorectal cancer for other gastrointestinal malignancies. 199 29

Soluble serum beta 2-microglobulin has been thought to result from membrane shedding by activated T-lymphocytes. This hypothesis could explain the increase of beta 2-microglobulin serum levels during virally induced mononucleosis, but not elevated levels as observed in other virally induced and in malignant diseases. In this paper we demonstrate that beta 2-microglobulin is a true secretory protein, and that its synthesis in hepatocytes is modulated by IFNs but not by IL-1. While the 45,000 MW HLA antigen can be found only in cell lysates, beta 2-microglobulin is shown to be secreted also into the culture medium like other secretory proteins (e.g. albumin-factor B-complement C3). Furthermore, interferon alpha (IFN alpha) as well as interferon gamma (IFN gamma) directly stimulate, in a dose- and time-dependent manner, beta 2-microglobulin synthesis by human hepatoma cells (Mz-Hep-1 and PLC/PRF5) and murine hepatocyte primary cultures. The increase of beta 2-microglobulin production induced by interferons is demonstrated at both the protein and the RNA level, indicating that interferon acts at a pretranslational level. The interferon effect on beta 2-microglobulin synthesis is specific since synthesis of secretory proteins like complement C3 or albumin, and of a structural protein like actin, remains unchanged. In contrast to IFN, IL-1, the main mediator of acute phase response, does not change beta 2-M biosynthesis rate. These data indicate that (i) beta 2-microglobulin is a secretory protein, (ii) IFNs but not IL-1 can mediate increased beta 2-M serum levels, and (iii) the liver may be its primary source.
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PMID:Alpha- and gamma-interferon (IFN alpha, IFN gamma) but not interleukin-1 (IL-1) modulate synthesis and secretion of beta 2-microglobulin by hepatocytes. 245 38

Signal Transducer and Activator of Transcription 3 (Stat3) is a latent protein activated in response to various cytokines and growth factors. It is believed that Stat3 is a key signaling molecule involved in the regulation of acute phase gene expression by interleukin 6 (IL-6) in hepatocytes. We report that both IL-6 and interferon gamma (IFN gamma) up-regulate the expression of Stat3 on both mRNA and protein levels in rat and human hepatoma cells. The effect of IL-6 and IFN gamma on Stat3 mRNA expression was time- and dose-dependent. Other factors, including IL-1, TNF alpha, EGF, Dexamethasone and PMA, did not have any effect on Stat3 mRNA expression. Moreover, we show that the rapid induction of Stat3 expression by IL-6 and IFN gamma was independent of ongoing protein synthesis, suggesting regulation by Stat3 and Stat1, respectively.
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PMID:Activation of signal transducer and activator of transcription-3 (Stat3) expression by interferon-gamma and interleukin-6 in hepatoma cells. 748 23

We investigated the expression of intercellular adhesion molecule 1 (ICAM-1) in ex vivo human hepatocellular carcinoma (HCC) cells and in vitro in eight liver cancer cell lines, including six HCC cell lines and two combined hepatocholangiocarcinoma (CHC) cell lines. Immunohistochemistry showed the expression of ICAM-1 on the HCC cell surface with honeycomblike appearance in most cases (96.2%). On the other hand, hepatocytes in noncancerous areas did not express ICAM-1, except those hepatocytes in the periportal and intra-acinar areas with inflammation. Immunohistochemical study on cultured cells revealed that four cultured HCC cell lines and one CHC cell line constitutively expressed ICAM-1 on the cell surface and in the cytoplasm. Flow cytometric analysis revealed that immunostain-positive cells expressed surface ICAM-1 with more than a 90% positive cell rate, and their expressions were upregulated by incubation of cells with inflammatory cytokines, such as interferon alfa, interferon gamma, tumor necrosis factor-alpha, and interleukin 1 beta. Soluble ICAM-1 was detected in supernatants of cell lines expressing cell surface ICAM-1 expression, and was increased in amounts 2- to 20-fold by inflammatory cytokines. These findings suggest that liver cancer cells in ex vivo may express not only surface but also a soluble form of ICAM-1, differently from normal hepatocytes, and that both expressions are upregulated by inflammatory cytokines.
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PMID:Expression of intercellular adhesion molecule 1 in human hepatocellular carcinoma. 748 78

Approximately 5% of the world population is infected by the hepatitis B virus (HBV) that causes a necroinflammatory liver disease of variable duration and severity. Chronically infected patients with active liver disease carry a high risk of developing cirrhosis and hepatocellular carcinoma. The immune response to HBV-encoded antigens is responsible both for viral clearance and for disease pathogenesis during this infection. While the humoral antibody response to viral envelope antigens contributes to the clearance of circulating virus particles, the cellular immune response to the envelope, nucleocapsid, and polymerase antigens eliminates infected cells. The class I- and class II-restricted T cell responses to the virus are vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and the responses are relatively weak and more narrowly focused in chronically infected patients who do not. The pathogenetic and antiviral potential of the cytotoxic T lymphocyte (CTL) response to HBV has been demonstrated by the induction of a severe necroinflammatory liver disease following the adoptive transfer of HBsAg-specific CTL into HBV transgenic mice, and by the noncytolytic suppression of viral gene expression and replication in the same animals by a posttranscriptional mechanism mediated by interferon gamma, tumor necrosis factor alpha, and interleukin 2. The dominant cause of viral persistence during HBV infection is the development of a weak antiviral immune response to the viral antigens. While neonatal tolerance probably plays an important role in viral persistence in patients infected at birth, the basis for poor responsiveness in adult-onset infection is not well understood and requires further analysis. Viral evasion by epitope inactivation and T cell receptor antagonism may contribute to the worsening of viral persistence in the setting of an ineffective immune response, as can the incomplete downregulation of viral gene expression and the infection of immunologically privileged tissues. Chronic liver cell injury and the attendant inflammatory and regenerative responses create the mutagenic and mitogenic stimuli for the development of DNA damage that can cause hepatocellular carcinoma. Elucidation of the immunological and virological basis for HBV persistence may yield immunotherapeutic and antiviral strategies to terminate chronic HBV infection and reduce the risk of its life-threatening sequellae.
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PMID:Hepatitis B virus immunopathogenesis. 761 25

Transcription of rat serine proteinase inhibitor 3 (SPI-3) gene is rapidly induced in the liver in response to inflammation. Treatment of rat hepatoma H-35 cells with interferon gamma (INF gamma) results in the immediate induction of this gene, with its 147 bp-long promoter being sufficient for activation. Within this promoter we have identified an IFN gamma-responsive element which maps to the signal transducer and activator of transcription (Stat)3-binding site. Mutation of this element causes a loss of responsiveness to IFN gamma, whereas fusion to a heterologous promoter confers a positive response on IFN gamma. The latter apparently induces the binding of a protein, identified as Stat1, to the described element, which gradually decreases within 24 h. Thus the induction of the SPI-3 gene by IFN gamma correlates with the binding of Stat1 to a specific element which, in turn, binds Stat3 in response to interleukin 6.
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PMID:Activation of the rat serine proteinase inhibitor 3 gene by interferon gamma via the interleukin 6-responsive element. 761 83

The effect of mouse interferon gamma (IFNg) on the proliferation of Hepa-1c1c7, mouse hepatoma cells was analyzed by means of [3H]thymidine incorporation. IFNg did not suppress the proliferation of Hepa-1c1c7 cells cultivated alone, however, it effectively suppressed in coculture with B6C3F1 mouse hepatocytes and in IFNg-treated mouse hepatocyte-conditioned media. Suppression of proliferation of hepatoma cells was detected only in the IFNg-treated hepatocyte-conditioned media but not in the control hepatocyte-conditioned media. The magnitude of suppression depended upon the amount of IFNg used in the preparation of conditioned media. The suppressive effect of IFNg-treated hepatocyte-conditioned media was retained by an ultrafilteration membrane (M.W. cut off 30,000), and its activity was abrogated by trypsin digestion and heat treatment. These results suggest that IFNg-treated mouse hepatocytes may release a soluble mediator(s) which suppressed the proliferation of hepatoma cells and that IFNg interactions with hepatocytes could be important to the antitumor defense mechanisms of the liver.
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PMID:Suppressed proliferation of mouse hepatoma cells by conditioned media from interferon gamma-treated hepatocytes. 766 11


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