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)

CD147 molecule is reported to be correlated with the malignancy of some cancers; however, it remains unclear whether it is involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the function of HAb18G/CD147, a member of CD147 family, and its antibodies, HAb18 and LICARTIN, in HCC invasion and metastasis. We observed that HAb18G/CD147 gene silence in HCC cells significantly decreased the secretion of matrix metalloproteinase (MMP) and the invasive potential of HCC cells (P < 0.001). MMP silence in HCC cells also significantly suppressed the invasion of the cells when cocultured with fibroblasts; however, its inhibitory effect was significantly weaker than that of both HAb18G/CD147 silence in HCC cells and that of MMP silence in fibroblasts (P < 0.001). Blocking theHAb18G/CD147 molecule on HCC cells with HAb18 monoclonal antibody resulted in a similar suppressive effect on MMP secretion and cell invasion, but with no significant effects on the cell growth. (131)I-labeled HAb18 F(ab')(2) (LICARTIN), however, significantly inhibited the in vitro growth of HCC cells (P < 0.001). In an orthotopic model of HCC in nude mice, HAb18 and LICARTIN treatment effectively reduced the tumor growth and metastasis as well as the expression of three major factors in the HCC microenviroment (MMPs, vascular endothelial growth factor, and fibroblast surface protein) in the paracancer tissues. Overall, these results suggest that HAb18G/CD147 plays an important role in HCC invasion and metastasis mainly via modulating fibroblasts, as well as HCC cells themselves to disrupt the HCC microenviroment. LICARTIN can be used as a drug targeting to HAb18G/CD147 in antimetastasis and recurrence therapy of HCC.
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PMID:HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. 1757 19

Clinical observations suggest that hepatocyte growth factor (HGF) can promote invasion and metastasis in hepatocellular carcinoma. In this study, we found that HGF-stimulated invasion of SK-Hep-1 cells, together with increased expression of matrix metalloproteinase (MMP)-9. CHM-1 was identified from 2-phenyl-4-quinolone derivatives to potently inhibit HGF-induced cell invasion, proteolytic activity, and expression of MMP-9. CHM-1 significantly inhibited tyrosine autophosphorylation of c-Met induced by HGF. CHM-1 also suppressed HGF-induced Akt phosphorylation, and NF-kappaB activation, the downstream regulators of HGF/c-Met signaling, resulting in the inhibition of MMP-9. Thus, we suggest that CHM-1 is a potential therapeutic agent against tumor invasion.
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PMID:CHM-1 inhibits hepatocyte growth factor-induced invasion of SK-Hep-1 human hepatocellular carcinoma cells by suppressing matrix metalloproteinase-9 expression. 1768 59

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), which is a plasma membrane glycoprotein enriched on the surface of many malignant tumors promotes adhesion, invasion and metastasis of tumor cells. In addition, tumor-associated CD147 also induces vascular endothelial growth factors (VEGFs) expression. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hca-F with highly metastatic potential in the lymph nodes, we used an RNA interference (RNAi) approach to silence CD147 expression. The results showed that CD147 depletion in Hca-F cells resulted in the significantly decreased expression of matrix metalloproteinase-11 (MMP-11), VEGF-A at both mRNA and protein levels. The reduced CD147 expression also attenuated the invasive, adhesive, metastatic ability of Hca-F cells to lymph nodes both in vitro and in vivo. Our current findings reveal that the tumor biological marker CD147 functionally mediates MMP-11, VEGF-A expression and tumor lymphatic metastasis.
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PMID:CD147 depletion down-regulates matrix metalloproteinase-11, vascular endothelial growth factor-A expression and the lymphatic metastasis potential of murine hepatocarcinoma Hca-F cells. 1769 20

Expression patterns of matrix metalloproteinase-9 (MMP-9) and its specific inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), are closely correlated with physiological and pathological processes characterized by the degradation and accumulation of the extracellular matrix (ECM). Both, activated MMP-9 and pro-MMP-9 can bind to TIMP-1, and most cell types secrete MMP-9 in complex with TIMP-1. Utilizing immunofluorescence, we observed intracellular co-localization of MMP-9 and TIMP-1 in stimulated human fibrosarcoma cells. In the present study we searched for the origin of the complex formation between the latent enzyme and its specific inhibitor on a subcellular level. Fluorescence resonance energy transfer (FRET) between the fluorescently labeled enzyme and its inhibitor in co-transfected cells were measured. MMP-9 and TIMP-1 were fused to cyan (CFP) and yellow (YFP) variants of the green fluorescent protein and transiently expressed in human hepatoma cells. The intracellular distribution of fluorescently labeled TIMP-1 and MMP-9 was analyzed by confocal laser scanning microscopy. Intracellular complex formation in the Golgi apparatus was verified, demonstrating FRET between MMP-9-CFP and TIMP-1-YFP. Our data provide evidence that the proMMP-9-TIMP-1 complex is already present in the Golgi apparatus. This may be of significance for a number of intracellular and extracellular biochemical processes involving proMMP-9. However, the magnitude and functional relevance of this finding remain unknown.
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PMID:Latent MMP-9 is bound to TIMP-1 before secretion. 1797 16

The discoidin domain receptor (DDR) is a class of receptor tyrosine kinases that binds to several collagens. DDR1 is widely expressed in fast-growing invasive tumors of the breast, ovary, esophagus, brain and lung. However, there is little information on the expression of DDR1 in hepatocellular carcinoma (HCC) or its function in migration and invasion. Western blot analysis was performed to determine if four HCC cell lines (HLE, Huh-7, HepG2 and SH-J1) express DDR1. The HLE and Huh-7 cell lines were transfected with two isoforms of DDR1, DDR1a and DDR1b. Immunoprecipitation for DDR1 was then performed. Migration and invasion assays were carried out and the number of migrating cells was counted in 6 randomly selected fields per well under an optical microscope. Zymography was used to determine the level of the matrix metalloproteinase (MMP)-2 and -9 expression. DDR1 was expressed in all four cell lines. In the migration assay, the number of migrating cells was significantly higher in the DDR1a- or DDR1b-overexpressing HLE and Huh-7 cells, particularly after collagen type I stimulation (P<0.001). Collagen type I stimulation activated DDR1. In the invasion assay, there was a significantly higher number of invading cells in the DDR1a- or DDR1b-overexpressing HLE cells and DDR1a-overexpressing Huh-7 cells than in the control (P<0.01). The DDR1a- and DDR1b-overexpressing HLE cells showed a remarkable increase in the MMP-9 and -2 expression, particularly the active MMP-2. The DDR1a- and DDR1b-overexpressing Huh-7 cells showed a slight increase in the MMP-9 and -2 expression. The increased invasiveness of the HCC may be associated with the overexpression of either DDR1a or DDR1b mediated by MMP-2 and -9. Although this study provided one possible mechanism for the invasion of HCC cells, more studies are needed to understand the signal through which DDR1a and DDR1b act in invasion.
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PMID:Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. 1798 27

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein-coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein-coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by beta-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma.
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PMID:Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells. 1802 79

Genetic variants in matrix metalloproteinase (MMP) gene may influence the biological function of these enzymes and change their role in carcinogenesis and progression. The effect of MMP2 C-1306T and MMP9 C-1562T polymorphisms on genetic susceptibility has been investigated in various kinds of cancer. However, the relationship between these polymorphisms and risk of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been reported. The present study was designed to investigate the association of these two loci with the risk of HCC recurrence in 93 HCC patients treated with LT. Genotyping was performed using direct DNA sequencing. For MMP2 C-1306T variant, patients with CT heterozygous conferred a 58% reduction in recurrence risk (risk ratio: 0.419; 95% confidence interval: 0.177-0.994). The mean recurrence-free survival for CT genotype was significantly longer than that for homozygous CC patients (30.4 vs 19.3 months, p = 0.019). However, no association was found between MMP9 C-1562T polymorphisms and recurrence of HCC (p = 0.259). These findings suggest that MMP2 promoter polymorphisms may provide some predictive value for HCC recurrence after LT.
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PMID:MMP2 promoter polymorphism (C-1306T) and risk of recurrence in patients with hepatocellular carcinoma after transplantation. 1817 74

CDC25A is a cell cycle-activating phosphatase that promotes transition from the G1 to S phase. We previously reported that overexpression of CDC25A in human hepatocellular carcinoma (HCC) tissue samples was associated with poor prognosis. In this study, we attempted suppression of CDC25A in HCC cells to elucidate the therapeutic potential of this approach. Administration of CDC25A antisense (AS) oligonucleotide resulted in 25-50% inhibition of cell growth at 48 h, G0-G1 arrest, and significant inhibition of cancer cell invasion. To elucidate the underlying mechanism of the inhibitory effects of HCC cell invasion, we examined several invasion-associated molecules, and we found that membrane-type 3 (MT3)-matrix metalloproteinase (MMP) mRNA was greatly reduced following treatment with AS oligonucleotide to CDC25A or siRNA treatment. Notably, screening of a panel of gastrointestinal cancer cells indicated that MT3-MMP was generally expressed by HCC cells, whereas other cell types did not express this type of matrix metalloproteinase so frequently. We also found that CDC25A facilitated cellular differentiation by increasing albumin expression in the PLC cell line. These results suggest that CDC25A, by inhibiting HCC growth and invasion, may be a feasible therapeutic target for human HCC.
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PMID:CDC25A inhibition suppresses the growth and invasion of human hepatocellular carcinoma cells. 1820 80

Lycopene has been shown to inhibit tumor metastasis in vitro, but it is unclear whether lycopene is antimetastatic in vivo. Here, nude mice were orally supplemented 2 times per week for 12 wk with a low or high dose of lycopene [1 or 20 mg/kg body weight (BW)] or with beta-carotene (20 mg/kg BW). Two weeks after the beginning of supplementation, mice were injected once with human hepatoma SK-Hep-1 cells via the tail vein. Plasma levels of matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) increased gradually in tumor-injected mice (tumor controls) following tumor injection but were markedly lowered by lycopene or beta-carotene supplementation. Ten weeks after tumor injection, mice were killed and tumor metastasis was found to be confined to the lungs. Compared with the tumor controls, high-lycopene supplementation lowered the mean number of tumors from 14 +/- 8 to 3 +/- 5 (P < 0.05) and decreased tumor cross-sectional areas by 62% (P < 0.05). High-lycopene supplementation also decreased the positive rate of proliferating cellular nuclear antigen (PCNA), the level of VEGF, and protein expressions of PCNA, MMP-9, and VEGF in lung tissues. However, high-lycopene increased the protein expression of nm23-H1 (an antimetastatic gene) by 133% (P < 0.001). For most variables measured, effects of lycopene were dose dependent and the effect of beta-carotene was between those of high-dose and low-dose lycopene. These results show that lycopene supplementation reduces experimental tumor metastasis in vivo and suggest that such an action is associated with attenuation of tumor invasion, proliferation, and angiogenesis.
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PMID:Lycopene inhibits experimental metastasis of human hepatoma SK-Hep-1 cells in athymic nude mice. 1893 33

CD147, also named as extracelluar matrix metalloproteinase inducer (EMMPRIN), has been proved to be involved in several aspects of tumor progression. In addition to its ability to induce vascular endothelial growth factor (VEGF) production, it confers resistance to some chemotherapeutic drugs. To investigate the possible role of CD147 in the mouse hepatocarcinoma cell line Hepa1-6 with no metastatic potential in the lymph nodes, we used RNA interference (RNAi) approach to silence CD147 expression. The results showed that silencing of CD147 in Hepa1-6 cells significantly impeded the expression of VEGF-A at both mRNA and protein levels. The siRNA-treated cells exhibited significantly decreased growth ability when compared with control cells. Colony formation of CD147 deficient cells was dramatically inhibited in soft agar, and tumorigenicity was reduced in nude mice. Furthermore, the downregulation of CD147 expression also sensitized cells to be more sensitive to curcumin. These results suggested that CD147 might be a potential target for therapeutic antitumor drugs.
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PMID:CD147 regulates vascular endothelial growth factor-A expression, tumorigenicity, and chemosensitivity to curcumin in hepatocellular carcinoma. 1837 92


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