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)

A new human hepatocellular carcinoma (HCC) cell line with a highly metastatic potential was established from subcutaneous xenograft of a metastatic model of human HCC in nude mice (LCI-D20) by means of alternating cell culture in vitro and growth in nude mice. The line, designated MHCC97, has been cultivated for 18 months and subcultured for more than 90 passages. The line was showed to be of human origin by karyotype analysis. The cells were either grown as compact colonies (in clusters) or as a monolayered sheet with about 31 h of population-doubling time, exhibited typical malignant epithelial in morphology and were positive for alpha-fetoprotein (AFP). Flow cytometric analysis of the cell DNA content showed an aneuploid pattern, and its index was 1.5 as compared to that of normal human peripheral blood lymphocytes. Karyotypic analyses of G- and C-banding techniques revealed that all cells presented chromosome abnormalities in number and structure. The number of cell line MHCC97 chromosome ranged from 59 to 65 with a modal number of 60 and 61. At least two common chromosome markers, i(1q) and der(4)t(4;?)(4pter-->q35::?), were present in all cells, and deletion of Y chromosome also occurred in all cells. The subcutaneous and intrahepatic xenografts were formed and metastatic lesions in lungs were found after the cells were inoculated into nude mice. The rate of metastasis to lungs was 100% using orthotopic inoculation. Reverse transcription polymerase chain reaction products revealed positive expressions of integrin alpha5 and beta1, urokinase type plasminogen activator receptor (uPAR), vascular endothelial growth factor and nm23-H1 mRNAs of cell line MHCC97. Immunostaining of c-Met, uPAR showed strongly positive in both subcutaneous xenografts and lung metastatic lesions; while positive in xenografts and negative in metastatic lesions for integrin alpha5, beta1. E-cadherin and P53 was not expressed either in xenograft or in the metastatic lesions. PCR products of HBsAg and HBxAg were both positive. The cell line MHCC97 still retained some characteristic features of original tumour. Establishment of cell line MHCC97 should be beneficial to the studies of HCC metastatic mechanisms.
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PMID:New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. 1055 51

Nitric oxide (NO) regulates production of vascular endothelial growth factor (VEGF) by normal and transformed cells. We demonstrate that NO donors may up-regulate the activity of the human VEGF promoter in normoxic human glioblastoma and hepatoma cells independent of a cyclic guanosine monophosphate-mediated pathway. Deletion and mutation analysis of the VEGF promoter indicates that the NO-responsive cis-elements are the hypoxia-inducible factor-1 (HIF-1) binding site and an adjacent ancillary sequence that is located immediately downstream within the hypoxia-response element (HRE). This work demonstrates that the HRE of this promoter is the primary target of NO. In addition, VEGF gene regulation by NO, as well as by hypoxia, is potentiated by the AP-1 element of the gene. Our study also reveals that NO and hypoxia induce an increase in HIF-1 binding activity and HIF-1alpha protein levels, both in the nucleus and the whole cell. These results suggest that there are common features of the NO and hypoxic pathways of VEGF induction, while in part, NO mediates gene transcription by a mechanism distinct from hypoxia. This is demonstrated by a difference in sensitivity to guanylate cyclase inhibitors and a different pattern of HIF-1 binding. These results show that there is a primary role for NO in the control of VEGF synthesis and in cell adaptations to hypoxia. (Blood. 2000;95:189-197)
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PMID:Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. 1060 2

The hepatitis B virus (HBV)-encoded transcriptional activator HBV-X protein (HBx) was known to be involved in hepatocarcinogenesis. Hepatocarcinogenesis generally included an active angiogenesis that was mainly considered to be due to a local hypoxia in liver tissues. However, the exact mechanisms of HBx-induced hepatocarcinogenesis were poorly understood. In this study, we examined the role of HBx in the increased angiogenesis and the possible regulating mechanisms of HBx by hypoxia. We demonstrated that HBx stimulated the transcription of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in HBx-stable transfectants. HBx-induced angiogenesis was confirmed by in vivo tumor angiogenesis assay, resulting in that the HBx transfectants increased the formation of new blood vessels compared to the control transfectants. Then, we demonstrated that the expression of HBx was enhanced after incubating HBV-infected hepatoma cells under hypoxia. Moreover, the activity of HBV enhancer 1 (Enh1) was increased when hepatoma cells transfected with the reporter plasmid containing HBV Enh1 were exposed to hypoxic conditions. These results strongly suggest that HBx may play a critical role in the hypoxia-induced angiogenesis through transcriptional activation of VEGF during hepatocarcinogenesis.
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PMID:Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. 1067 26

Tumor progression is angiogenesis dependent, and vascular endothelial growth factor (VEGF) is a key growth factor in this process. sVEGF concentrations in 44 patients with hepatocellular carcinoma (HCC) and 5 with benign liver lesions were determined with an enzyme-link immunoadsorbent assay system (ELISA). Reverse transcript-polymerase chain reaction (RT-PCR) was carried out on surgical specimens of 51 patients with HCC. The relative levels of VEGF mRNA expression were measured by determining a ratio between PCR products of VEGF and the endogenous internal standard gene b-actin. UEA-1 was histochemically used to count microvascularity in tumor tissue. Elevated sVEGF concentrations were found in patients with HCC (172.84+/-111.75 pg/ml) as compared to individuals with benign liver lesions (95.74+/-36.20 pg/ml, P<.05). Of 44 cases with HCC, sVEGF concentrations in the patients with PV-emboli or with poor-encapsulated tumors were significantly higher than in those without PV-emboli or with well-encapsulated tumors (P<0.05). The expression levels of VEGF mRNA in tumors with PV-emboli and in poor-encapsulated tumors were higher than in those without PV-emboli and in well-encapsulated tumors (P<0.05). Microvascular density in HCC tissues was significantly correlated with the expression levels of VEGF mRNA (P<0.01; r=0.7). Circulating VEGF was derived from HCC tissue. sVEGF concentrations could be a new marker for predicting the angiogenesis, invasion and metastasis of HCC.
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PMID:Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. 1074 78

To understand the relationship between the expression of vascular endothelial growth factor (VEGF) and the growth, metastasis of hepatocellular carcinoma (HCC), immunohistochemistry and Northern blot were used to investigate VEGF protein and mRNA in 21 cases of HCC with and without metastasis. VEGF protein was found in 8 of 9 cases with metastasis, whereas only in 4 of 12 cases without metastasis. The positive rate of the former was significantly higher than that in the latter. VEGF mRNA was detectable in both carcinoma and its surrounding liver tissues, but its level in the former was 2-3 times higher than that in the latter. In carcinoma with metastasis, the mRNA level was 5-6 times higher than that without metastasis. It is concluded that VEGF is closely related to the growth of HCC as well as its metastasis and it might be a useful indicator for the metastatic potential of HCC.
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PMID:Expression of vascular endothelial growth factor in hepatocellular carcinoma and its relationship to tumor growth and metastasis. 1080 93

Flt-1 (VEGF receptor-1) and KDR/Flk-1 (VEGF receptor-2) are the high-affinity receptors for the angiogenesis factor, vascular endothelial growth factor (VEGF). VEGF expression has been confirmed in human hepatocellular carcinoma (HCC), and VEGF is thought to be involved in the angiogenesis within HCC tissues. However, expressions of VEGF receptors in HCC have not been reported. We immunohistochemically examined expressions and localizations of Flt-1 and KDR in 28 surgically resected HCC tissues. In non-cancerous area, Flt-1 and KDR were mainly found in macrophages including Kupffer cells; both receptors were found in vascular endothelial cells in the portal veins and arteries within portal tracts; and KDR was also found in some sinusoidal endothelial cells. In cancerous area, Flt-1 and KDR were found in some macrophages, and also in the endothelial cells of intratumoral blood vessels. In 25 moderately and/or poorly differentiated HCCs, KDR expression in the blood space endothelial cells was clear and continuous in 20 cases, and focal in 5 cases. These results suggest that there would be an angiogenesis mechanism via VEGF/Flt-1 or VEGF/KDR in HCC, and the VEGF/KDR system would take a more important role.
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PMID:Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. 1085 33

Hammerhead-type ribozymes are often utilized to suppress the expression of target genes. We evaluated the efficacy of an anti-vascular endothelial growth factor (VEGF) hammerhead-type ribozyme against GUC at exon 1 of the VEGF gene in a cell-free system (in vitro) as well as in the hepatocellular carcinoma cell line HLF (in vivo). The anti-VEGF ribozyme (alphaVRz) specifically cleaved synthetic VEGF RNA substrate, but not other triplet sequences of VEGF RNA substrate in vitro. When the alphaVRz was introduced into HLF cells, the ribozyme suppressed not only VEGF mRNA level but also that of VEGF protein. These results suggest that this ribozyme selectively inhibits VEGF gene expression in human hepatocellular carcinoma cells.
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PMID:Hammerhead ribozyme specifically inhibits vascular endothelial growth factor gene expression in a human hepatocellular carcinoma cell line. 1093 89

The vascular endothelial growth factor-A (VEGF-A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF-A are mediated through flt-1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than those of VEGF-A nAb. The autophosphorylation of KDR/ Flk-1 in the peritoneal wall was almost completely abolished by KDR/ Flk-1 nAb, whereas a certain level of activation was still shown by VEGF-A nAb treatment. Another VEGF-family, VEGF-C, which also binds KDR/Flk-1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk-1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF-A, VEGF-C may also be involved in the malignant ascites formation via KDR/ Flk-1 activation.
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PMID:The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model. 1128 48

We previously reported that the retroviral vector expressing the herpes simplex virus-thymidine kinase gene under the control of 0.3-kb human alpha-fetoprotein (AFP) gene promoter (AF0.3) provided the cytotoxicity to ganciclovir (GCV) in high-AFP-producing human hepatoma cells but not in low-AFP-producing cells. Therefore, specific enhancement of AFP promoter activity is likely to be required to induce enough cytotoxicity in low-AFP-producing hepatoma cells. In this study, we constructed a hybrid promoter, [HRE]AF, in which a 0.4-kb fragment of human vascular endothelial growth factor 5'-flanking sequences containing hypoxia-responsive element (HRE) was fused to AF0.3 promoter. By means of the reporter gene transfection assay, hypoxia-inducible transcriptions that were mediated by [HRE]AF promoter were detected in low- and non-AFP-producing human hepatoma cells, but not in nonhepatoma cells. When the herpes simplex virus-thymidine kinase gene controlled by [HRE]AF promoter was transduced into hepatoma and nonhepatoma cells by a retroviral vector, the exposure to 1% O2 induced GCV cytotoxicity specifically in the hepatoma cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors consisting of the virus-infected hepatoma cells gradually disappeared by GCV administration. These results indicate that the hypoxia-inducible enhancer of the human vascular endothelial growth factor gene, which is directly linked to human AFP promoter, involves selective and enhanced tumoricidal activity in gene therapy for hepatocellular carcinoma.
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PMID:Gene therapy targeting for hepatocellular carcinoma: selective and enhanced suicide gene expression regulated by a hypoxia-inducible enhancer linked to a human alpha-fetoprotein promoter. 1130 81

Angiotensin-I converting enzyme (ACE) inhibitor is used widely as an antihypertensive agent, and it has been suggested recently that it decreases the risk of cancer (A. F. Lever et al., Lancet, 352: 179-184, 1998). In this study, we examined the effect of several ACE inhibitors and angiotensin-II type 1 receptor (AT(1)-R) antagonists on tumor development and angiogenesis in a murine hepatocellular carcinoma model. Among ACE inhibitors, perindopril appeared to be a potent inhibitor of tumor development and angiogenesis, whereas AT(1)-R antagonists did not exert such an inhibitory effect. The inhibitory effect of perindopril was achieved even on established tumors. The level of the potent angiogenic factor, vascular endothelial growth factor (VEGF), in the tumor was significantly suppressed by perindopril. In vitro studies showed that perindopril-derived active form, perindoprilat, suppressed the endothelial cell tubule formation. Perindoprilat treatment also significantly inhibited VEGF mRNA expression in BNL-HCC cells in vitro. These results showed that the ACE inhibitor perindopril inhibited tumor development and angiogenesis independent from AT(1)-R blockage, and that VEGF alternation may be involved in the mechanism of this inhibitory effect. Because perindopril is widely used in clinical practice, it may represent an effective new strategy for anticancer therapy.
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PMID:The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. 1130 59


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