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)

We isolated human intercrine reduced in hepatomas (hIRH) as a mRNA whose expression was reduced in differential displays from human hepatocellular carcinoma. hIRH is equivalent to the alpha-chemokine SDF-1alpha/PBSF. We have previously demonstrated on Northern blot analysis that although hIRH mRNA expression is common in human normal tissues, it is absent from pre-malignant colonic adenomas and from 27 human malignant cell lines. However, there are no reports on the mRNA status of hIRH in other human cancers. The present study was designed to investigate semi-quantitatively the expression of hIRH/SDF-1alpha mRNA in hepatocellular carcinoma and digestive tract cancers by reverse transcription-polymerase chain reaction (RT-PCR). The expression of hIRH/SDF-1alpha in the majority of cancer tissues analyzed was markedly reduced compared with that in adjacent non-cancer tissue. RT-PCR was more sensitive than Northern blots in the detection of hIRH mRNA. The average (mean +/- SE) tumor/normal (T/N) ratio determined by RT-PCR was 0.40 +/- 0.07 in 10 pairs of hepatoma, 0.38 +/- 0.09 in 14 pairs of colon cancers, 0.43 +/- 0.07 in 10 pairs of esophageal cancers and 0.70 +/- 0.09 in 26 pairs of gastric cancers. As a control, the mean G3PDH T/N ratio was 1.16 +/- 0.06. The distribution of T/N ratios was significantly different between gastric cancer and the other cancers, but there was no correlation between hIRH/SDF-1alpha expression and clinicopathological characteristics in gastric cancer. Our findings demonstrate that hIRH/SDF-1alpha expression is reduced in the majority of gastrointestinal tumors.
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PMID:Reduced expression of the CXC chemokine hIRH/SDF-1alpha mRNA in hepatoma and digestive tract cancer. 939 42

We have recently demonstrated by Northern blot and RT-PCR that the mRNA expression of the alpha-chemokine hIRH/SDF-1alpha is reduced in hepatocellular carcinoma (HCC), several digestive tract cancers and premalignant colon adenomas, and that its receptor CXCR4 mRNA expression is reduced in HCC. Here we investigate the expression of CXCR4 mRNA expression in several digestive tract cancers and hepatitis C viral (HCV) infected liver, a premalignant condition. There was no difference in the CXCR4 mRNA expression in colon, esophageal or gastric cancers compared to non-cancerous tissues. This is significantly different from the reduced expression we have seen with hepatocellular carcinoma (p<0.05). To better refine regional tumor or hepatic cytokine mRNA analysis within a biopsy sample we describe a micro-isolation technique for RNA extraction from portal and triad areas of liver biopsies or other small malignant or non-malignant biopsy samples suitable for use in RT-PCR and differential display reactions. In HCV liver biopsies, the expression of hIRH and its receptor CXCR4 mRNA, corrected for G3PDH, was not significantly different from that of control non-HCV (steatosis) biopsies. CXCR4 is expressed on leukocytes and its expression was predicted to correlate with hepatic inflammation. CXCR4 receptor mRNA expression did correlate significantly with that of its ligand hIRH/SDF-1alpha (p=0.001), and with the severity of fibrosis (p<0.05), but not with portal inflammation (p<0.10), piecemeal necrosis (p<0.10), lobular inflammation (p>0.10), the presence of lymphoid aggregates (p>0.10), or the total histological activity index (p=0.07). There was no difference in expression of hIRH or CXCR4 between responders and non-responders to interferon (IFN) treatment, while as a control, the responder group of patients did show a higher expression of IFNalpha receptor than the non-responder group (p=0.05).
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PMID:CXCR4 mRNA expression in colon, esophageal and gastric cancers and hepatitis C infected liver. 1020 Mar 42

Chemotactic cytokines (chemokines) play an important role in the recruitment of lymphocytes to tissue by regulating cellular adhesion and transendothelial migration. This study examined the expression and function of CXC (human monokine induced by gamma-interferon [HuMig], interleukin-8 [IL-8], and interferon-inducible protein-10 [IP-10]) and CC (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, regulated upon activation normal T lymphocyte expressed and secreted (RANTES), and macrophage chemoattractant protein-1 [MCP-1]) chemokines and their respective receptors on lymphocytes infiltrating human liver tumors. Chemokine and chemokine receptor expression was assessed by immunohistochemistry, flow cytometry, in situ hybridization and ribonuclease (RNAse) protection assays and function by in vitro chemotaxis of tumor-derived lymphocytes to purified chemokines and to HepG2 tumor cell culture supernatants. Tumor-derived lymphocytes showed strong chemotactic responses to both CC and CXC chemokines in vitro and expressed high levels of CXCR3 (HuMig and IP-10 receptor) and CCR5 (RANTES, MIP-1alpha, and MIP-1beta receptor). Expansion of tumor-derived lymphocytes in recombinant IL-2 increased expression of CXCR3. The corresponding chemokines were detected on vascular endothelium (HuMig, IL-8, MIP-1alpha, and MIP-1beta) and sinusoidal endothelium (HuMig, MIP-1alpha, MIP-1beta) in hepatocellular carcinoma. In vitro, HepG2 cells secreted functional chemotactic factors for tumor-derived lymphocytes that could be inhibited using anti-CCR5 or anti-CXCR3 monoclonal antibodies (MoAbs). Thus, lymphocytes infiltrating human liver tumors express receptors for and respond to both CXC and CC chemokines. The relevant chemokine ligands are expressed in hepatocellular carcinoma (HCC), particularly HuMig, which was strongly expressed by tumor endothelium, suggesting that they play a role in lymphocyte recruitment to these tumors in vivo. The ability of HepG2 cells to secrete lymphocyte chemotactic factors in vitro suggests that the tumor contributes to lymphocyte recruitment in vivo.
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PMID:Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. 1038 45

The IFN-gamma-inducible proteins monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2) can contribute to IL-12-induced antiangiogenic and leukocyte-recruiting activities, but the extent to which leukocytes vs parenchymal cells in different organs contribute to the production of these molecules remains unclear. The results presented herein show that IFN-gamma-dependent induction of Mig and Crg-2 gene expression can occur in many nonlymphoid organs, and these genes are rapidly induced in purified hepatocytes isolated from mice treated with IL-2 plus IL-12, or from Hepa 1-6 hepatoma cells treated in vitro with IFN-gamma. In addition to depending on IFN-gamma, the ability of IL-12 or IL-2/IL-12 to induce Mig and Crg-2 gene expression in purified hepatocytes also is accompanied by the coordinate up-regulation of the IFN-gamma R alpha and beta-chains, in the absence of IL-12R components. Supernatants of primary hepatocytes obtained from mice treated in vivo with IL-2/IL-12 or from hepatocytes treated in vitro with IFN-gamma contain increased chemotactic activity for enriched human and mouse CD3(+) T cells, as well as mouse DX5(+) NK cells. The hepatocyte-derived chemotactic activity for mouse T cells but not NK cells was ablated by Abs specific for Mig and Crg-2. These results suggest that parenchymal cells in some organs may contribute substantially to initiation and/or amplification of inflammatory or antitumor responses.
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PMID:Primary hepatocytes from mice treated with IL-2/IL-12 produce T cell chemoattractant activity that is dependent on monokine induced by IFN-gamma (Mig) and chemokine responsive to gamma-2 (Crg-2). 1123 18

Expression of the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is absent from many carcinomas, including hepatomas. We note an early signalling defect in the hepatocellular carcinoma (HCC) cell line HepG2 that expresses the CXCR4 receptor and binds biotin-labelled SDF, but fails to stimulate downstream signalling events after engagement with SDF. In HepG2, the SDF/CXCR4 interaction did not result in calcium influx, phosphorylation and internalization of CXCR4, nor in a rapid phosphorylation of p44/42 MAP kinase. There were no CXCR4 mutations in the second chemokine binding loop or C terminal phosphorylation and internalization domains. The downstream signalling machinery in HepG2 appears to be intact since transfection of wild-type CXCR4 restored functional responsiveness. We conclude that HepG2 is unresponsive to SDF stimulation because of a defect located after receptor binding but before the activation of the signalling cascade. A hypothetical blocking molecule could hinder receptor internalization or CXCR4 signalling.
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PMID:Loss of chemokine SDF-1alpha-mediated CXCR4 signalling and receptor internalization in human hepatoma cell line HepG2. 1136 12

Liver-expressed chemokine (LEC)/CCL16 is a human CC chemokine selectively expressed in the liver. Here, we investigated its receptor usage by calcium mobilization and chemotactic assays using mouse L1.2 pre-B cell lines stably expressing a panel of 12 human chemokine receptors. At relatively high concentrations, LEC induced calcium mobilization and chemotaxis via CCR1 and CCR2. LEC also induced calcium mobilization, but marginal chemotaxis via CCR5. Consistently, LEC was found to bind to CCR1, CCR2 and CCR5 with relatively low affinities. The binding of LEC to CCR8 was much less significant. In spite of its binding to CCR5, LEC was unable to inhibit infection of an R5-type HIV-1 to activated human peripheral blood mononuclear cells even at high concentrations. In human liver sections, hepatocytes were strongly stained by anti-LEC antibody. HepG2, a human hepatocarcinoma cell line, was found to constitutively express LEC. LEC was also present in the plasma samples from healthy adult donors at relatively high concentrations (0.3--4 nM). Taken together, LEC is a new low-affinity functional ligand for CCR1, CCR2 and CCR5, and is constitutively expressed by liver parenchymal cells. The presence of LEC in normal plasma at relatively high concentrations may modulate inflammatory responses.
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PMID:Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes. 1147 Jul 72

Primary liver cancer and liver metastases from gastrointestinal tumors lack effective therapy. Gene therapy is a promising therapeutic approach and is based on the introduction of genetic material into cells to generate a curative biological effect. Adenoviral vectors can very efficiently transduce a wide variety of malignant epithelial cells both in vitro and in vivo. A variety of gene therapy-based anticancer strategies have been effective in animal tumor models, including replacement of tumor suppressor genes, selective activation of prodrugs, genetic immunotherapy, and antiangiogenic actions. Enzymes used for genetic activation include viral thymidine kinase (tk), which may activate nucleoside analogs such as ganciclovir. We and others have demonstrated the efficacy of the tk/ganciclovir system in the treatment of hepatocellular carcinoma and metastatic colorectal cancer in experimental models. Also, this strategy can be safely applied to patients with liver tumors. Interleukin-12 (IL-12) is among the most potent cytokines in stimulating antitumor immunity. In models of primary and metastatic liver cancer we showed that intratumoral administration of recombinant adenovirus encoding IL-12 activates natural killer cells, induces specific antitumor immunity, and displays a powerful antiangiogenic effect, resulting in tumor regression. There is a synergistic effect with the gene transfer of the chemokine IP-10. Also, intratumoral injection of either dendritic cells transfected ex vivo with recombinant adenovirus encoding IL-12 (Ad.IL-12) or an adenovirus coding for the CD40 ligand have shown an intense antitumor effect against experimental colorectal cancer. In summary, a variety of gene therapy strategies have been effective against animal models of gastrointestinal tumors. Clinical trials should determine whether human patients can be treated safely and effectively by such strategies.
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PMID:Gene therapy of hepatocellular carcinoma and gastrointestinal tumors. 1209 23

The CXCL12 / CXCR4 system may be important in carcinoma. Expression of the alpha-chemokine SDF-1alpha (stromal cell derived factor-1alpha) / CXCL12 mRNA is reduced in many carcinomas, yet its tissue protein expression may guide metastasis. Here we first compare the mRNA and protein expression of CXCL12 and its receptor CXCR4 in human liver, hepatocellular carcinoma, and malignant cell lines, and then assess cell cycle variation in CXCR4 expression. CXCR4 mRNA was present in most normal human tissues and malignant cell lines; it was only marginally reduced in hepatomas, while CXCL12 was markedly reduced, P < 0.0001. Immuno-histochemical staining of adjacent non-malignant liver showed regional CXCR4 cytoplasmic and cell-surface staining, limited to those hepatocytes around the central vein, a distribution resembling that of CXCL12. CXCL12 protein was not present in hepatocellular carcinoma cells in vivo, nor was cytoplasmic CXCR4 staining; nuclear CXCR4 protein expression in some malignant hepatocytes and CXCR4 staining of capillary endothelial cells around tumor cells were noted. In some malignant cell lines that had no CXCL12 on northern blots CXCL12 was weakly detectable by RT-PCR or protein staining in the cytoplasm of a few cells. With a view to future manipulation of CXCL12 / CXCR4 expression and growth we noted that in HT-29 cells CXCR4 protein expression was less on confluent than on non-confluent cells and varied during the cell cycle. Higher expression was associated most closely with the percentage of cells in the S-phase and inversely with the percentage of cells in the G1-phase. Treatment of HT-29 cells with butyrate reduced CXCR4 cell surface expression and reduced the percentage of cells in S-phase. In summary, CXCL12 protein expression parallels its mRNA, being markedly reduced in malignant cell lines and hepatomas; in liver, the regional distributions of CXCL12 and cytoplasmic CXCR4 are similar; finally, in HT-29, CXCR4 expression correlates with the S-phase of the cell cycle and is reduced during butyrate-induced differentiation.
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PMID:Regional expression of CXCL12/CXCR4 in liver and hepatocellular carcinoma and cell-cycle variation during in vitro differentiation. 1214 45

The efficacy of the suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system for the treatment of cancer is limited because of the insufficient gene transfer and the low killing activity. To enhance the antitumor activity, we determined whether recombinant adenovirus vector (rAd)s expressing both HSV-tk and monocyte chemoattractant protein-1 (MCP-1) genes could potentiate the destruction of hepatocellular carcinoma (HCC). The rAd Ad-tk-MCP1 harboring HSV-tk and MCP-1 genes in sequence under the universal CAG promoter was constructed with a bicistronic unit including the encephalomyocarditis virus-internal ribosomal entry site. The levels of HSV-tk expression and GCV-sensitive tumoricidal activity of Ad-tk-MCP1 were comparable to those of rAd expressing HSV-tk alone. The growth of subcutaneous tumors in athymic nude mice was markedly suppressed when tumors were treated with Ad-tk-MCP1 as opposed to another bicistronic vector Ad-MCP1-tk, rAd expressing either HSV-tk or MCP-1, or both of these vectors. The antitumor effects of Ad-tkMCP1 may be dependent on the activation of macrophages, since the recruitment of macrophages was observed tumor necrosis factor-alpha production was enhanced in the tumor tissue. Furthermore, the enhanced antitumor effect was abolished by inactivating macrophages with carrageenan treatment. These results demonstrated that a bicistronic rAd harboring both suicide and chemokine genes in sequence exerted the enhanced, macrophage-dependent, antitumor effects in a model of HCC and support the use of this strategy for the treatment of HCC.
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PMID:Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma. 1267 98

Macrophage inflammatory protein (MIP-3alpha) is a CC chemokine that attracts immature dendritic cells and lymphocytes and is thought to play a role in the pathogenesis of inflammation and carcinogenesis. However, nothing is known about the clinical significance or prognostic importance of this chemokine in patients with cancer. The aim of this study was to assess the clinical factors influencing the levels of serum MIP-3alpha and to evaluate any possible prognostic importance of this chemokine. We further checked the possible source of MIP-3alpha in hepatocellular carcinoma (HCC). The levels of serum MIP-3alpha from 45 patients with HCC, 12 patients with liver cirrhosis (LC) and 45 patients with chronic hepatitis (CH) were measured by an enzyme immunoassay. A correlationship between different clinical parameters and the serum levels of MIP-3alpha was analyzed. Production of MIP-3alpha by human cancer cell lines and peripheral blood mononuclear cells (PBMC) was also estimated. The levels of serum MIP-3alpha were significantly higher in HCC than in LC (p=0.0214) and CH (p<0.0001). Cancer-related factors such as size of cancer nodules, levels of differentiation of HCC and the levels of alpha-fetoprotein were related with increased MIP-3alpha levels in HCC. Human cancer cell lines, but not PBMC from HCC patients, produced very high levels of MIP-3alpha in culture. The rate of recurrence of HCC after radio frequency ablation (RFA) was fewer in patients having lower pre-therapeutic levels of serum MIP-3alpha. An impact of cancer-related factors on the levels of serum MIP-3alpha in HCC is shown. Pre-therapeutic levels of serum MIP-3alpha may be used as a marker of prognosis of RFA therapy.
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PMID:Increased serum levels of macrophage inflammatory protein-3alpha in hepatocellular carcinoma: relationship with clinical factors and prognostic importance during therapy. 1268 96


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