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)

In order to obtain an HCC-selective drug delivery system, a novel functional lipid, which is cleaved by the protease activity of matrix metalloproteinase-2 (MMP-2), was developed. The amino group of dioleoylphosphatidylethanolamine (DOPE) was conjugated with PEGylated MMP-2 substrate peptide (Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln), and MMP-2-cleavable PEG-Peptide-DOPE (PEG-PD) was synthesized. When PEG-PD was incorporated in galactosylated liposomes (Gal-PEG-PD-liposomes), we expected that Gal-PEG-PD-liposomes would not be taken up by normal hepatocytes due to the steric hindrance effect, but would be activated around HCC cells by secreted MMPs. In the pretreatment by hMMP2 (1, 5, and 10mug/ml), an hMMP2 concentration-dependent higher uptake of Gal-PEG-PD-liposomes was observed in HepG2 cells, suggesting PEG-PD cleavage. In the presence of an excess of galactose, the uptake of Gal-PEG-PD-liposomes with hMMP2 was significantly inhibited, suggesting asialoglycoprotein receptor-mediated uptake of Gal-PEG-PD-liposomes following the PEG-PD cleavage. Pretreatment of Gal-PEG-PD-liposomes with the conditioned medium of B16BL6, which contained secreted MMPs, enhanced the binding to HepG2 cells, as in the case of hMMP-2 treatment. Moreover, the cytotoxicity of N(4)-octadecyl-1-beta-d-arabinofuranosylcytosine (NOAC) incorporated Gal-PEG-PD-liposomes was enhanced by hMMPs (5mug/ml) and its cytotoxicity was significantly reduced by the presence of an excess of galactose in HepG2 cells. In conclusion, Gal-PEG-PD-liposomes were successfully developed for novel HCC-selective targeting.
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PMID:Novel PEG-matrix metalloproteinase-2 cleavable peptide-lipid containing galactosylated liposomes for hepatocellular carcinoma-selective targeting. 1648 46

Lycopene, which is the predominant carotenoid in tomatoes and tomato-based foods, may protect humans against various cancers. Effects of lycopene on the adhesion, invasion, migration, and growth of the SK-Hep1 human hepatoma cell line were investigated. Lycopene inhibited cell growth in dose-dependent manners, with growth inhibition rates of 5% and 40% at 0.1 microM and 50 microM lycopene, respectively, after 24 hrs of incubation. Similarly, after 48 hrs of incubation, lycopene at 5 microM and 10 microM decreased the cell numbers by 30% and 40%, respectively. Lycopene decreased the gelatinolytic activities of both matrix metalloproteinase (MMP)-2 and MMP-9, which were secreted from the SK-Hep1 cells. Incubation of SK-Hep1 cells with 110 microM of lycopene for 60 mins significantly inhibited cell adhesion to the Matrigel-coated substrate in a concentration-dependent manner. To study invasion, SK-Hep1 cells were grown either on Matrigel-coated Transwell membranes or in 24-well plates. The cells were treated sequentially for 24 hrs with lycopene before the start of the invasion assays. Cell growth and death were assessed under the same conditions. The invasion of SK-Hep1 cells treated with lycopene was significantly reduced to 28.3% and 61.9% of the control levels at 5 microM and 10 microM lycopene, respectively (P < 0.05). In the migration assay, lycopene-treated cells showed lower levels of migration than untreated cells. These results demonstrate the antimetastatic properties of lycopene in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells.
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PMID:Inhibitory effects of lycopene on the adhesion, invasion, and migration of SK-Hep1 human hepatoma cells. 1651 80

Phenylethyl isothiocyanate (PEITC), a hydrolysis compound of gluconasturtiin, is metabolized to N-acetylcysteine (NAC)-PEITC in the body after the consumption of cruciferous vegetables. We observed an inhibitory effect of PEITC and its metabolite NAC-PEITC on cancer cell proliferation, adhesion, invasion, migration and metastasis in SK-Hep1 human hepatoma cells. PEITC and NAC-PEITC suppressed SK-Hep1 cell proliferation in a dose-dependent manner, and exposure to 10 microM PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%, respectively. NAC-PEITC inhibited cancer cell adhesion, invasion and migration to a similar or to an even larger degree than PEITC. The expression of matrix metalloproteinase (MMP) 2, MMP-9 and membrane type 1 matrix metalloproteinase (MT1-MMP) is a known risk factor for metastatic disease. Gelatin zymography analysis revealed a significant downregulation of MMP-2/MMP-9 protein expression in SK-Hep1 cells treated with 0.1-5 microM PEITC or NAC-PEITC. PEITC and NAC-PEITC treatment caused dose-dependent decreases in MMP-2/MMP-9 and MT1-MMP mRNA levels, as determined by reverse transcription polymerase chain reaction. PEITC and NAC-PEITC also increased the mRNA levels of tissue inhibitors of matrix metalloproteinase (TIMPs) 1 and 2. Our data suggest that this inhibition is mediated by downregulation of MMP and upregulation of TIMPs.
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PMID:Phenylethyl isothiocyanate and its N-acetylcysteine conjugate suppress the metastasis of SK-Hep1 human hepatoma cells. 1656 23

Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.
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PMID:Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. 1665 41

CD147 which is a regulator of matrix metalloproteinase (MMP) production on the surface of many malignant tumor cells, shows a highly specific association with caveolin-1 (Cav-1). As a result of heterogeneous N-glycosylation, CD147 exists in both highly glycosylated form, HG-CD147 ( approximately 40-60kDa) and lowly glycosylated form, LG-CD147 ( approximately 32kDa). This study investigated the possible role of Cav-1 in CD147 glycosylation in the HcaF, HcaP and Hepa1-6 mouse hepatocarcinoma cell lines, which have high, low and no metastatic potential in the lymph nodes, respectively, and in the normal mouse liver cell line IAR-20. Using an RNA interference (RNAi) strategy, we showed that the down-regulation of Cav-1 in Hca-F/RNAi cells could suppress the conversion of LG-CD147 to HG-CD147, down-regulate MMP-11 expression and decrease Hca-F/RNAi cell invasion. Conversely, a stable high expression of Cav-1 in Hepa1-6/Cav-1 cell could cause a specific increase of HG-CD147, up-regulate MMP-11 protein expression and enhance Hepa1-6/Cav-1 cell invasion. In conclusion, Cav-1 expression leads to an increased proportion of HG-CD147 relative to LG-CD147, increased production of MMP-11 and a higher invasive capability. Cav-1 is therefore proposed to act as both an oncogene and a tumor suppressor gene, and could represent a new potential target for gene therapy.
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PMID:Caveolin-1 up-regulates CD147 glycosylation and the invasive capability of murine hepatocarcinoma cell lines. 1670 20

HAb18G/CD147, a membrane spanning molecule and highly expressed in hepatocellular carcinoma (HCC) cells, was shown to stimulate the production of matrix metalloproteinases (MMPs) in the interaction of tumor cells and fibroblasts. Studies on the EMMPRIN/CD147 showed that CD147 extracellular domain is involved in the induction of MMPs. To study the biological molecular function of HAb18G/CD147 extracellular domain (HAb18G/CD147-ED) on production of MMPs following mediated tumor cell invasion, we isolated four novel monoclonal anibodies (MAbs)-1B3, 3B3, HAb18Gedomab1, and HAb18Gedomab2-against HAb18G/CD147-ED by immunization of BALB/c mice with purified HAb18G/CD147-ED fragments, which were efficiently expressed in Escherichia coli. Gelatin zymography and Boyden chamber assays were used to identify the production of MMPs in the co-cultured human fibroblast and HCC cells, and to quantify the migrated cells in the presence of the generated MAbs. The results showed that two MAbs (1B3 and 3B3) inhibited [corrected] the secretion of MMP-2 and [corrected] the HCC cell invasion, whereas the other two MAbs (HAb18Gedomab1 and HAb18Gedomab2) had reverse function [corrected] FCM additive assay showed that four MAbs recognized different epitopes of HAb18G/CD147-ED. Taken together, the results suggest that various regions of HAb18G/CD147-ED participated in the regulation of MMP secretion.
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PMID:Regulation of matrix metalloproteinase production and tumor cell invasion by four monoclonal antibodies against different epitopes of HAb18G/CD147 extracellular domain. 1670 5

This study is to investigate the molecular mechanism of radiation-enhanced cell invasiveness of hepatocellular carcinoma (HCC) correlating with clinical patients undergoing radiotherapy and subsequently developing metastasis. Three HCC cell lines (HepG2, Hep3B and Huh7) and normal hepatocyte cell line (CL-48) were irradiated with different doses. The effect of radiation on cell invasiveness was determined using the Boyden chamber assay. Radiation-enhanced invasion capability was evident in HCC cells but not in normal hepatocytes. Invasion was observed in gelatin-coated but not fibronectin-coated or type I collagen-coated membranes. Radiation upregulated matrix metalloproteinase-9 (MMP-9) mRNA level, MMP-9 protein level and MMP-9 activity. MMP-9 antisense oligonucleotides inhibited radiation-induced MMP-9 expression and thereby significantly inhibited radiation-induced HCC invasion. Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt chemical inhibitors LY294002 and wortmannin suppressed radiation-induced MMP-9 mRNA expression. Transient transfection with dominant-negative Akt plasmid also showed that the PI3K/Akt-signaling pathway was involved in this radiation-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed radiation enhanced MMP-9 promoter activity completely. PI3K/Akt chemical inhibitors inhibited radiation-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that sublethal dose of radiation could enhance HCC cell invasiveness by MMP-9 expression through the PI3K/Akt/NF-kappaB signal transduction pathway.
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PMID:Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. 1673 16

Halofuginone, an inhibitor of collagen synthesis, appears to be a promising antitumoral drug in preclinical studies. We used a relevant rat model of autochthonous, chemically induced, spontaneously metastasizing hepatocellular carcinoma (HCC) to test the efficacy of halofuginone on tumor progression and matrix metalloproteinase (MMP) expression. Following sequential administration of diethylnitrosamine and N-nitrosomorpholine for 14 weeks, all animals developed HCC and then received halofuginone or its solvent for 10 weeks. The final number of liver tumors was lower in the halofuginone group than in the solvent group (57.2 +/- 4.6 vs 68 +/- 5.0; P < .01). The percentage of the lung surface infiltrated by metastasis was much smaller in the halofuginone group (0.3 +/- 0.2%) than in the solvent group (13.5 +/- 10.1%; P < .02). MMP-9 activity was decreased in the halofuginone group by 89% and 63% in non-neoplastic parts of the liver and tumor, respectively. The percentage of active MMP-2 was reduced by 90% in non-neoplastic parts of the liver and by 61% in tumors. This was likely subsequent to a decreased expression of both MMP-14 and tissue inhibitor of matrix metalloproteinase-2, which are required for pro-MMP-2 activation. These results, obtained from a clinically relevant model, further suggest the potential benefit of halofuginone in HCC.
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PMID:Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition. 1675 23

Using a phage display approach, we identified AWYPLPP peptide as a specific peptide ligand that binds to the cell surface of highly metastatic human hepatocellular carcinoma (HCC). Moreover, the peptide was able to promote in vitro invasion of highly metastatic HCC cells by activating matrix metalloproteinase-9 and in vivo lung metastasis of HCC tumors. These results indicate that AWYPLPP peptide likely recognizes a novel receptor that is selectively expressed on the cell surface of highly metastatic HCC and mediates cellular activities associated with the invasive phenotype. Identification of the receptor for the AWYPLPP peptide may provide new insights into the molecular mechanism of HCC metastasis.
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PMID:A novel peptide that selectively binds highly metastatic hepatocellular carcinoma cell surface is related to invasion and metastasis. 1680 73

Vasculogenic mimicry (VM) has increasingly been recognized as a form of angiogenesis. In VM, epithelial cells are integrated into the malignant tumor vasculature. An association has been observed between VM and poor clinical prognosis in some malignant tumors. However, whether VM is present and clinically significant in hepatocellular carcinoma (HCC) is unknown. In this study, we determined whether VM was present in HCC and whether it was associated with tumor grade, invasion and metastasis, and survival duration. We collected paraffin-embedded HCC tumor samples, along with complete clinical and pathologic data for all the cases, and performed immunohistochemical staining for CD31, CD105 (endoglin), hepatocyte, vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9. The VM status was compared with the clinical and pathological data using statistical tests. Kaplan-Meier survival analysis and log-rank test were used to compare survival durations between patients with and without VM. The VM vessel cells were CD31 and CD105-negative and hepatocyte and vascular endothelial growth factor-positive, showing that they were not derived from endothelial cells but were HCC tumor cells. Patients with VM had a higher metastasis rate than did those without VM (P=0.003). Consistent with this finding, MMP-2 and MMP-9 were present in all the VM cases but were found less frequently in non-VM cases (P<0.05). The Kaplan-Meier survival analysis showed that patients in the VM group had a significantly shorter survival duration than did those in the non-VM group. In conclusion, VM is a marker of poor clinical prognosis in HCC: Its presence may be associated with a high tumor grade, invasion and metastasis, and short survival.
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PMID:Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma. 1696 81


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