UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An imbalance between the proteolytic activity of matrix metalloproteinase-2 (MMP-2) and the tissue inhibitor of MMP-2 (TIMP-2) is responsible for degradation of extracellular matrix (ECM) components and plays a critical role in tumor invasion and in metastasis formation. The occurrence of intra-hepatic metastasis, which severely affects prognosis and long-term survival, is commonly observed in the course of hepatocellular carcinoma (HCC). We investigated the expression of MT1-MMP in tissues, whereas both MMP-2 and TIMP-2 were evaluated in the sera and tissues (primary and metastatic nodules) of HCC patients with and without metastasis, whose clinical outcome was followed over a 2-year period. MT1-MMP expression was similar among primary nodule tissues of patients with and without metastasis. Serum and tissue levels of MMP-2 were not statistically different between patients with and without metastasis, but MMP-2 was concentrated at the invasive edge of the metastatic tissue. On the contrary, serum and tissue levels of TIMP-2 were significantly higher in HCC patients without metastasis than in those with. This situation was not only observed in the primary HCC tissues, but also in the metastatic nodules. These results correlate with the clinical outcome, because more than 90% of the patients with high levels of TIMP-2 were still alive after 2 years, whereas less than 30% with low levels of TIMP-2 had survived. Furthermore, we found a strict correlation between tissue and serum levels of TIMP-2, this suggesting that a MMP-2/TIMP-2 imbalance and in particular TIMP-2 levels, could represent an important prognostic factor in patients with HCC.
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PMID:Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. 1180 2

AIM:To investigate the predictors for recurrence or metastasis of HCC, and to evaluate the effect of antiangiogenic therapy on the growth of transplantable human HCC in nude mice.METHODS:RT-PCR was used to measure the expression of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in 56 pairs of nontumorous liver and tumor samples. Sixty blood samples from human HCC were examined by nested RT-PCR to find out AFP mRNA. Recombinant human endostatin and polyclonal antibody against VEGF were administered to treat human HCC transplanted in nude mice.RESULTS:Thirty of 56 HCC samples showed stronger expression of MMP9 in tumorous tissues than in nontumorous tissues. Fifteen of the 26 patients with relative expression level of MMP-9 more than 0.34 developed tumor recurrence or metastasis, whereas only 7 of 30 patients with relative expression level less than 0.34 developed tumor recurrence (P < 0.05). There was no significant difference in the relative expression level of VEGF between patients with postoperative recurrence or metastasis and those without recurrence. AFP mRNA was detectable in 53.3% of patients with HCC. The sensitivity and specificity of AFP mRNA as a marker to detect hematogenous dissemination of HCC cells was 81.8% and 84.4%, respectively. Recombinant human endostatin and polyclonal antibody against VEGF inhibited the growth of transplantable HCC in nude mice by 52.2% and 45.7%, respectively.CONCLUSION: MMP-9 expression in HCC correlates with the postoperative recurrence or metastasis of HCC. Patients with high level of MMP-9 expression in HCC are susceptible to metastasis.AFP mRNA could serve as an indicator of hematogenous spreading of HCC cells in circulation and a predictor of recurrence or metastasis of HCC. Antiangiogenesis may be an adjuvant therapy for HCC.
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PMID:Recurrence or metastasis of HCC:predictors, early detection and experimental antiangiogenic therapy. 1181 24

Increased plasma levels of matrix metalloproteinase (MMP)-9 have been shown in cancerous diseases including hepatocellular carcinoma (HCC). Our present aim was to examine whether the measurement of plasma MMP-9 concentration is clinically useful for assessing or monitoring HCC patients. We measured the plasma MMP-9 concentrations in 47 HCC patients, and compared the results with the clinicopathologic features. The plasma MMP-9 levels in patients with HCC were significantly higher than those in the normal controls. The plasma levels of MMP-9 were not related to the size of HCC tumor, the grade of histological differentiation and the serum alpha-fetoprotein level. The plasma levels of MMP-9 were not significantly changed after the effective treatment of HCC tumors. In conclusion, the plasma MMP-9 test was of little value for assessing or monitoring HCC patients.
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PMID:Plasma matrix metalloproteinase-9 (gelatinase B) in patients with hepatocellular carcinoma. 1195 88

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are considered to exert antitumor actions in a variety of cancer cells, although the effects are unlikely entirely due to COX inhibition. Because clinical observations suggest that hepatocyte growth factor (HGF) can promote metastasis of hepatoma cells while stimulating tumor invasiveness, we investigated the effect of aspirin and NS-398, a selective COX-2 inhibitor, on HGF-mediated invasiveness of HepG2 human hepatoma cells. HGF stimulated the invasiveness of HepG2 cells in Matrigel cell invasion assay, together with increased expression of matrix metalloproteinase (MMP) 9. Addition of aspirin or NS-398, similar to PD98059, which acts as a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), an upstream kinase regulating extracellular signal-regulated kinase (ERK)1/2, abrogated such actions of HGF without affecting cell viability. Aspirin and NS-398, in contrast to PD98059, did not suppress ERK1/2 phosphorylation induced by HGF. However, both agents inhibited the kinase activity of ERK1/2 induced by HGF and repressed HGF-induced phosphorylation of 90-kd ribosomal S6 kinase (RSK) and Elk-1, key downstream substrates of ERK1/2, resulting in the suppression of transcriptional activity of Elk-1 as well as nuclear factor kappaB (NF-kappaB) and AP-1, which are involved in MMP-9 gene regulation. In conclusion, our results suggest that aspirin and NS-398 inhibit HGF-induced invasiveness of HepG2 human hepatoma cells through ERK1/2.
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PMID:Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. 1198 61

Alpha2-HS glycoprotein (fetuin) is a major plasma glycoprotein predominantly synthesized by the liver. We have previously demonstrated that human fetuin produced by hepatocellular carcinoma cells can activate the matrix metalloproteinase MMP-9 (gelatinase-B). Stromelysin-1 (MMP-3) is over-expressed in murine skin tumors and is associated with a metastatic cell phenotype. We hypothesize that fetuin plays a role in tumor progression of cell types which by themselves do not have the ability to express fetuin. Immunohistochemical staining revealed that fetuin surrounds the tumor cells in murine squamous cell carcinoma tumor specimens, similar to the expression pattern previously seen for MMP-3. The physical association of fetuin and MMP-3 was demonstrated by immunoprecipitation of radiolabeled fetuin by antibodies to MMP-3. Fetuin facilitates the conversion of pro-MMP-3 to its active form, although this effect is indirect. The association of iodinated fetuin to the cell surface of intact cultured cells derived from a murine tumor with squamous (B9) and spindle (A5) morphologies was determined by binding experiments and Scatchard analysis. Fetuin binds with Bmax values in the range of 1.26-2.1 (mean = 1.7) fmol/1 x 10(5) cells for A5 cells, and 1.5-1.7 (mean = 1.6) fmol/1 x 10(5) cells for B9 cells. The mean KD was 0.46+/-0.19 nmol for both A5 and B9 cells. Our data therefore are consistent with the model that fetuin binds to the cell surface of tumor cells and acts to localize and anchor other molecules important during tumor progression to the plasma membrane.
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PMID:Interactions of alpha2-HS-glycoprotein (fetuin) with MMP-3 and murine squamous cell carcinoma cells. 1237 Jul 42

The hepatitis B virus (HBV) is a major cause of human liver disease, including hepatocellular carcinoma (HCC). The prognosis for HCC is largely dependent on the clinicopathological characteristics regarding invasion and metastasis. Enhanced matrix metalloproteinase-9 (MMP-9) expression has been implicated as playing an important role in metastasis and invasion of HCC. However, the relationship between HBV infection and MMP-9 expression in HCC is currently poorly understood. We report here on a study of the levels of MMP-9 and MMP-2 expression in human fetal liver tissue, rat liver tissue, and Chang, HepG2, and Hep3B cells by gelatin zymography. Among these sources, Hep3B cells, which contain the integrated hepatitis B viral genome, continuously secrete the hepatitis B viral surface antigen, and express HBV genomic RNA, expressed high levels of proMMP-9, and a small amount of active MMP-9 was detected in Hep3B cells as assayed by zymography. We investigated the issue of whether HBV infection affects MMP-9 expression, which is known to play an important role in HCC invasion and metastasis. As a first step, human fetal hepatocyte (HFH) and HepG2 (HCC origin, HBV not detected) cells were subjected to infection with HBV, and the resulting infected cells successfully established are hereafter referred to as HFH-T2 and HepG2-HBV. The expression of MMP-9 was upregulated by the infected HBV in HFH-T2 and HepG2-HBV cells, as assayed by zymography, Northern blot, and Western blot analysis, and small amounts of active MMP-9 were detected in HFH-T2 and HepG2-HBV cells as assayed by zymography. The activation of the immature proMMP-9 to the mature MMP-9 could be induced by plasmin treatment. The activation of proMMP-9 was increased to a greater extent with plasmin treatment than without plasmin in HFH-T2 and HepG2-HBV cells but the addition of recombinant TIMP-1 inhibited the activation of proMMP-9. Finally, the addition of plasmin to the invasion assay using Matrigel resulted in an increase in invasiveness of HFH-T2 and HepG2-HBV cells, as well as MMP-9 activation, but the treatment with TIMP-1 inhibited the invasiveness of HFH-T2 and HepG2-HBV cells as well as MMP-9 activation. We conclude from these findings that HBV infection of hepatocytes and HepG2 cells affected the upregulation of MMP-9 expression and MMP-9 activation and, thus, increased the invasion potential by plasmin. To our knowledge, this is a first report showing that an HBV infection is linked to the upregulation of MMP-9 in HCC.
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PMID:Enhanced expression of matrix metalloproteinase-9 by hepatitis B virus infection in liver cells. 1246 65

Hepatocellular carcinoma is strongly associated with chronic infection by the hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis. HBx is often the only HBV protein detected in hepatic tumor cells; however, its contribution to tumor invasion and metastasis has not been established so far. In this work, we show that HBx enhances tumor cell invasion, both in vivo and in vitro. The increased invasive capacity induced by HBx is mediated by an upregulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, which in turn activates matrix metalloproteinase-2. Induction of both MT1-MMP expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2) activity. In addition, HBx upregulates the expression of COX-2, which is mediated by the transcriptional activation of the COX-2 gene promoter in a nuclear factor of activated T cell-dependent (NF-AT-dependent) manner. These results demonstrate the ability of HBx to promote tumor cell invasion by a mechanism involving the upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of action of this viral protein and its involvement in tumor metastasis and recurrence of hepatocellular carcinoma.
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PMID:The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. 1248 33

Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as follows: hepatocyte growth factor activator was only detected in malignant tissue but not cirrhotic liver or normal liver. Although hepatocyte growth factor was detected in most samples, it was significantly elevated in 5/9 hepatocellular carcinomas. Furthermore, 8/9 fibrolamellar hepatocellular carcinomas demonstrated hepatocyte growth factor receptor levels similar to normal, whereas 8/9 hepatocellular carcinomas and 11/12 cirrhotic livers exhibited either an increase or decrease. In contrast, active matrix metalloproteinase-2, which was absent in normal liver, was elevated in fibrolamellar hepatocellular carcinoma as compared to cirrhotic liver and conventional hepatocellular carcinoma. Surprisingly, 10/12 cirrhotic livers and 2/4 fibrolamellar hepatocellular carcinomas but only 1/9 hepatocellular carcinomas were enriched for plasmin. The combined data suggest that the hepatocyte growth factor and plasmin systems tend to be operative in hepatocellular carcinoma and cirrhotic liver, more than fibrolamellar hepatocellular carcinoma. Furthermore, matrix turnover appears to be a more prominent feature of fibrolamellar hepatocellular carcinoma. These findings provide insight into the behavioral differences between hepatocellular carcinoma and the fibrolamellar variant.
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PMID:HGF, MET, and matrix-related proteases in hepatocellular carcinoma, fibrolamellar variant, cirrhotic and normal liver. 1252 8

Various extracts prepared from stems of Euonymus alatus were tested for cytotoxic activity on human hepatocellular carcinoma cell line, Hep3B cells using the XTT assay method. Also, the extracts were investigated the inhibitory effects on matrix metalloproteinase (MMP)-9 activity using gelatin zymography. The methanol extract, hexane and ethyl acetate fraction exhibited weak cytotoxic activity (IC(50) of >100 microg/ml). However, butanol (IC(50)=65 microg/ml) and chloroform (IC(50)=85 microg/ml) fraction exhibited strongly cytotoxic activity. Gelatin zymography showed that the Hep3B cells secreted matrix metalloproteinase (MMP), probably including MMP-9, which may be involved in tumor cell invasion and metastasis. The butanol fraction showed stronger inhibitory effect of proteolytic activity than other fractions. Also, the butanol fraction was able to decrease the proteolytic activity of MMP-9 in a concentration-dependent manner on zymography. These results suggest that the butanol fraction from E. alatus has highly inhibitory effect on MMP-9 in comparatively low cytotoxicity.
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PMID:Inhibitory effect of methanol extract of Euonymus alatus on matrix metalloproteinase-9. 1257 16

The epidermal growth factor receptor (EGFR) is highly expressed in many human tumors and provides a new target for anticancer drug development. EGFR-targeted agents have shown promising antitumor activity in preclinical and clinical trials. However, little is yet known about the effect of these new agents on tumor metastasis. Here, we investigate the effects of ZD1839 (Iressa), a selective EGFR tyrosine kinase inhibitor, on the metastatic properties of murine hepatocellular carcinoma CBO140C12. ZD1839 inhibited not only cell growth but also epidermal growth factor-induced chemotactic migration and production of active matrix metalloproteinase-9 in vitro. In mice, orthotopic implantation of a fragment of CBO140C12 tumor into the liver resulted in the formation of a solitary tumor nodule and intrahepatic metastasis. ZD1839, given p.o., inhibited growth of the implanted tumor and intrahepatic metastasis by approximately 50%. These results indicate that EGFR signaling plays an important role in tumor metastasis and that ZD1839 is effective at inhibiting intrahepatic metastasis.
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PMID:ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. 1281 35

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