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)

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

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

Assessment of angiogenesis may yield important information for an effective antiangiogenic treatment for hepatocellular carcinoma (HCC) because HCC is characteristically hypervascular We examined the relationship of microvessel density (MVD), vascular endothelial growth factor (VEGF), and VEGF receptors Flt-1 and Flk-1/KDR in 50 patients with HCC and in 3 hepatoma cell lines. VEGF messenger RNA (mRNA) was overexpressed in 26 tumors (52%), and the 3 VEGF isoforms (121, 165, and 189) were present in high frequencies. Flt-1 mRNA was overexpressed in 34 tumors (68%), with levels significantly increased in HCCs compared with the nontumorous livers. Tumor Flt-1 mRNA significantly correlated with tumor VEGF mRNA levels. Within the group of tumors 8.5 cm or less in diameter, tumors with intrahepatic metastasis in the form of tumor microsatellite formation had significantly higher VEGF mRNA levels. MVD assessed by immunohistochemical analysis with CD34 antibody was inversely related to tumor size. Angiogenesis as assessed by MVD and tumor VEGF expression seems to have a more important role in tumor growth and intrahepatic metastasis in smaller HCCs. The differential up-regulation of Flt-1 suggests that it may have an important role in angiogenesis in HCC.
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PMID:Microvessel density, vascular endothelial growth factor and its receptors Flt-1 and Flk-1/KDR in hepatocellular carcinoma. 1176 72

The levels of expression of various genes were altered in cellular transformants with manipulation of expression of single genes. Vascular endothelial growth factor A (VEGF-A) is a key molecule for tumor progression, although it is unclear how VEGF-A expression regulates various genes. Multiple gene expression levels were evaluated using cDNA arrays in a human hepatocellular carcinoma cell line (HLF) with suppression of the VEGF-A gene by anti-VEGF-A ribozyme (alphaVRz). The ribozyme-mediated suppression of VEGF-A gene solely up-regulated matrix metalloproteinase 1 (MMP1) gene level in HLF/alphaVRz. Levels of expression of other members of MMP family or tissue inhibitors of MMPs did not show any alteration. These results suggested that intracellular suppression of VEGF-A gene was specifically linked to up-regulation of MMP1 in human hepatocellular carcinoma cells.
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PMID:Ribozyme mediated suppression of vascular endothelial growth factor gene expression enhances matrix metalloproteinase 1 expression in a human hepatocellular carcinoma cell line. 1206 53

Cancer is a genomic functional disease with features of oncogene activation and tumor suppressor inactivation. These genomic features have resulted in the limited effectiveness of conventional therapies and therefore forced considerable efforts to explore new types of anticancer agents. It has been clear that chemically synthesized or in vivo-expressed short interfering RNA (siRNA) can specifically and effectively direct homology-dependent post-transcriptional gene silencing. In the present study, we intended to investigate whether siRNA could suppress the proliferation of human cancer cells through interfering oncogene activities and recovering the functions of tumor-suppressor gene. Single siRNA or combinatorial siRNAs were successfully transfected into HeLa cells, lung adenocarcinoma cells, hepatoma cells, ovarian carcinoma cells, and melanoma cells with cationic lipid complexes. These siRNA molecules not only specifically knocked down their cognate targets such as bcl-2, cdk-2, mdm-2, pkc-alpha, tgf-beta1, H-ras, vegf, and GFP mRNAs, but also effectively suppressed the proliferation of cancer cells to different extents. These data suggest that (1) all these human cancer cells preserve RNAi machinery; (2) chemically synthesized and vector-driven siRNAs can be incorporated into intrinsic RNAi system for silencing target mRNA molecules; and (3) the combination of different siRNAs inhibits the growth and proliferation of cancer cells.
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PMID:siRNA agents inhibit oncogene expression and attenuate human tumor cell growth. 1456 90

VEGF, a potent angiogenic growth factor, is up-regulated in many tumors including human breast tumors and stimulates growth of vascular networks that support tumor growth and metastasis. We previously reported that natural and synthetic progestins (P) increased VEGF mRNA and protein levels in progesterone receptor (PR) containing T47-D human breast cancer cells in a PR dependent manner, but not in PR positive ZR-75 and MCF-7, or in PR negative MDA-MB-231 cells. This indicated that factors beside PR are involved in progesterone-dependent VEGF regulation. We, therefore, tested additional tumor cell lines reported to contain PR for progestin-dependent VEGF induction. Out of nine PR-positive breast tumor cell lines, progestins induced VEGF in three cell lines that lack wild-type p53 (T47-D, BT-474, and HCC-1428) but not in cell lines that contained the wild-type p53 protein. The T47-D and BT-474 cells express mutant p53, while the p53 protein is absent HCC-1428 cells. The anti-progestin RU-486 blocked progestin-dependent induction of VEGF in T47-D and BT-474 cells but not in HCC-1428 cells. However, RU-486 partially blocked medroxyprogesterone acetate-dependent induction of VEGF in HCC-1428 cells. Estrogen receptor (ER) and PR agonists and antagonists also induce VEGF in HCC-1428 cells and this effect was partially blocked by anti-estrogen ICI-182, 780. Progestin-dependent VEGF induction was completely inhibited by PRIMA-1-activated p53 in all cell-types, but progestin-dependent transcription of a progesterone-regulated minimal promoter was only partially inhibited. PRIMA-1 induced activation of p53 in tumor cell lines was confirmed with a p53-responsive p21 reporter plasmid and by detecting increased levels of p21 proteins in cell lysates. PRIMA-1 induced p53 protein in the HCC-1428 cells while levels of mutant p53 protein in T47-D and BT-474 remained unaltered. Progestin-dependent induction of VEGF was also inhibited by stable transfection of wild-type p53 in T47-D cells. These results are consistent with the hypothesis that wild-type p53 blocks progestin-dependent induction of VEGF in breast cancer cells and this may be a novel anti-angiogenic mechanism for controlling the growth of progestin-dependent tumors.
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PMID:p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells. 1586 Feb 60

In order to investigate the inhibitory effects on the vascular endothelial growth factor (VEGF) expression and cell growth in hapatocellular carcinoma (HCC) by blocking HIF-1alpha and Smad3 binding site in the VEGF promoter, antisense oligodeoxynucleotides (ASODN) were designed to block HIF-1alpha and Smad3 binding site in the VEGF promoter. Different concentrations of ASODN and ODN were transfected into HCC cells respectively. The expression of VEGF mRNA and protein was detected by SABC, Western blot and RT-PCR techniques and the inhibitory effects on the expression of VEGF and cell growth of the HCC cells stimulated by the supernatants were determined by using MTT method. Immunohistochestry revealed that after co-inoculation of hepatocellular carcinoma cells with different concentrations of ODN and ASODN for 48 h, there was no significant difference in the expression of VEGF protein between ODN group and control group (P > 0.05), but there was significant difference between ASODN group and control group (P < 0.05). At a concentration of 10 micromol/L ASODN, the difference was very significant (P < 0.01). Western blot and RT-PCR revealed that, after treatment for 48 h at a concentration of 10 micromol/L. the integral gray levels and RNA odds were 59743.2 +/- 10412.5 and 0.783 +/- 0.032 in ODN group, and 38694.5 +/- 10925.1 and 0.468 +/- 0.015 in ASODN group, respectively, with the difference being very significant (P < 0.01). Antisense ODN could inhibit the growth of HCC cells in a concentration-dependent manner. It was concluded that anti-gene technique of aiming at HIF-1alpha action site in the VEGF promoter could suppress the VEGF expression and inhibit HCC cell growth, and it is promising that anti-gene technique works as a new gene therapeutic tool for anti-angiogenesis of HCC.
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PMID:Inhibition of the VEGF expression and cell growth in hepatocellular carcinoma by blocking HIF-1alpha and Smad3 binding site in VEGF promoter. 1671 28

The aim of the present study was to detect the correlation between the expression of vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2), ephrinB2 and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and carcinogenesis or portal vein tumor thrombus (PVTT) formation in human hepatocellular carcinoma (HCC). The expression of VEGF, Ang2, ephrinB2 and EG-VEGF was detected by RT-PCR in 54 cases HCC without PVTT (group A), 9 cases HCC with PVTT (group B), 10 normal liver tissues (group D) and 10 cirrhosis tissues (group C). The samples were also stained with CD34 by immunohistochemistry. Quantitation of microvessel density (MVD) and semi-quantitation of VEGF, Ang2, ephrinB2 and EG-VEGF expression were analyzed to find the relations. The MVD was 146.69 +/- 77.79, 214.07 +/- 54.41, 32.85 +/- 8.49 and 34.83 +/- 8.29 in group A-D respectively with significant difference (F = 19.77, P = 0.000). The MVD in group A was higher than that in group C P = 0.006, but lower than that in group B P < or = 0.05 or 0.01. The expression levels of VEGF165, VEGF189, Ang2 and EG-VEGF mRNA were significantly different among the groups. The expression levels of VEGF165, Ang2 and EG-VEGF mRNA in group A were all higher than those in group C, but lower than those in group B P < 0.05 or 0.01. The MVD was significantly correlated with VEGF165, VEGF189, Ang2 and EG-VEGF mRNA with Spearman's related coefficient being 0.764, 0.510, 0.640 and 0.366 in HCC (P = 0.000, 0.000 0.000 and 0.003). In conclusion VEGF, Ang2 and EG-VEGF mRNA may play a role in angiogenesis and carcinogenesis of HCC. They can promote PVTT formation in HCC by modulating angiogenesis.
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PMID:Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma. 1716 81

In this study the small interfering RNA(siRNA) targeting human VEGF effectively inhibited the expression of VEGF in human hepatoma cell line, SMMC7721, and could dramatically decrease the tumorigenicity of SMMC7721 s.c. xenograft tumor. Chemically synthesized siRNA targeting VEGF was transiently transfected into SMMC7721 cells by lipofectamine, RT-PCR and Elisa analysis suggested that the expression of VEGF mRNA and secreted protein in SMMC7721 cells with VEGF siRNA transfection were suppressed with inhibition rates of 76.16% and 96.28% respectively compared with negative control, but the growth rate of SMMC 7721 cells with VEGF siRNA transfection was the same as the control cells. In vivo test, siRNA was injected directly into implanted tumors and the tumors volume were calculated at different time interval. Result showed that VEGF siRNA greatly inhibited the growth of tumors tissues, which was consistent with decrease of VEGF mRNA and protein compared with control. In addition, the VEGF siRNA-treated group exhibited obvious signs of necrosis compared with control.
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PMID:[Reduction of tumorigenicity of SMMC7721 hepatoma cell line by VEGF siRNA]. 1825 31


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