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)

We have characterized a transcriptional enhancer of the human urokinase-type plasminogen activator (uPA) gene and found a regulatory element required for co-operation between a PEA3--AP-1 element and an AP-1 site in the enhancer. We designated this regulatory element co-operation mediator (COM). Both the PEA3--AP-1 element, the AP-1 site and the COM are required for efficient phorbol ester induction of transcription from the uPA promoter in the HepG2 hepatoma cell line. We show that the COM is also required for co-operation between the PEA3--AP-1 element and a glucocorticoid response element, both in the presence or absence of TPA, indicating that the COM is generally capable of mediating synergism between inducible enhancer elements. The COM contains multiple overlapping binding sites for nuclear proteins, designated uPA enhancer factors 1-4 (UEF-1-4). We have identified putative binding sites for UEF-1, -2 and -3. The UEF-1 and -3 sites in the uPA enhancer are highly conserved between species. We demonstrate the binding of UEF-3 to the NIP element, a previously characterized regulatory element in the human interleukin-3 and stromelysin promoters, suggesting that this factor plays a role in regulation of a variety of genes.
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PMID:A regulatory element that mediates co-operation between a PEA3-AP-1 element and an AP-1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells. 133 May 39

Metalloproteinase inhibitors were surveyed with the culture media of 19 kinds of human tumor cell lines, using transin (rat stromelysin) as the target enzyme. This survey showed that most of the cell lines more or less secreted inhibitor activity, and that a human hepatoma cell line, HLE, secreted an extremely high inhibitor activity into the culture medium. Two kinds of metalloproteinase inhibitors were purified from the serum-free conditioned medium of HLE cells. The major inhibitor, which showed a single protein band with a molecular weight (Mr) of 21,000 (21k) (nonreduced) or 24k (reduced) on SDS-polyacrylamide gel electrophoresis, was identified as TIMP-2 (tissue inhibitor of metalloproteinases-2) by the analysis of its N-terminal amino acid sequence. The other was immunologically identified as TIMP. Purified TIMP-2 inhibited the activities of transin, matrin (pump-1), Mr 72k gelatinase, and interstitial collagenase with 1:1 stoichiometry. When the latent precursor form (Mr 57k) of transin was incubated with p-aminophenylmercuric acetate as an activating reagent, TIMP-2 inhibited the conversion of the intermediate form (Mr 45k) into the mature enzyme (Mr 42k). This indicated that TIMP-2 regulates not only the activity of the mature enzyme but also the autolytic processing of the proenzyme. TIMP-2 also inhibited in vitro tumor invasion through reconstituted basement membrane (matrigel) in chemotaxis chambers, showing that the metalloproteinase inhibitors as well as the extracellular matrix metalloproteinases are involved in tumor invasion through basement membrane and other extracellular matrices.
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PMID:Efficient purification of TIMP-2 from culture medium conditioned by human hepatoma cell line, and its inhibitory effects on metalloproteinases and in vitro tumor invasion. 166 1

Antibodies were raised against seven major matrix metalloproteinases: stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), interstitial collagenase (MMP-1), M(r) 72,000 type IV collagenase (72 kDa type IV collagenase, MMP-2), M(r) 92,000 type IV collagenase (92 kDa type IV collagenase, MMP-9) and matrilysin (PUMP, MMP-7) as well as against prolyl 4-hydroxylase, to study the expression of these collagenolytic enzymes in normal liver in relation to the activity of collagen synthesis. Tissue samples of four normal human livers, three hepatocellular carcinomas and one cholangiocellular carcinoma were analysed. In normal liver we found expression of stromelysin-1, stromelysin-3, interstitial collagenase, M(r) 72,000 and M(r) 92,000 type IV collagenases and varying expression of prolyl 4-hydroxylase. Stromelysin-2 was inconsistently detectable; matrilysin was not found. In hepatocellular carcinoma the expression pattern of matrix metalloproteinases showed only minor changes compared with the normal tissue; stronger signals than in normal tissue were seen for stromelysin-1, and stromelysin-2 was also strongly positive. M(r) 72,000 and M(r) 92,000 type IV collagenases and interstitial collagenase were less strongly expressed; stromelysin-3 was unchanged. Expression of prolyl 4-hydroxylase was also increased compared with normal liver. Matrilysin was only seen in cholangiocellular carcinoma, which showed a completely different pattern of matrix metalloproteinase expression. Our results show that metalloproteinases are expressed in human liver with much greater abundance than previously described. Their expression pattern is not changed fundamentally in hepatocellular carcinoma but is completely different from that of other tumour tissues such as cholangiocellular carcinoma.
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PMID:Expression pattern of matrix metalloproteinases in human liver. 763 22

Tissue inhibitor of metalloproteinases (TIMP-1) is a potent inhibitor of activated matrix metalloproteinases (MMP) such as collagenase, stromelysin, and gelatinase, and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells. Since various cytokines and growth factors can modify the production of MMP and TIMP-1, we explored the action of oncostatin M (OM), a unique lymphocyte- and monocyte-derived cytokine, on expression of these proteins. We examined the regulation of TIMP-1 expression in cultured human fibroblasts by cytokines including OM, IL-6, leukemia inhibitory factor (LIF), and IL-1 alpha. When used at levels of 5 to 50 ng/ml, OM, IL-6, LIF, and IL-1 alpha elevated the TIMP-1 expression at the RNA level in fibroblasts of lung or synovial origin. Interestingly, OM stimulation resulted in highest levels of TIMP-1 RNA and protein synthesis. However, unlike IL-1 alpha, the cytokines OM, IL-6, and LIF did not induce MMP or PGE2 release. OM also enhanced TIMP-1 mRNA levels in the H2981 lung carcinoma and HepG2 hepatoma cell lines. The results suggest that OM as well as IL-6 and LIF, other cytokines acting through similar receptor pathways, may act to inhibit net MMP activity by specifically up-regulating TIMP-1 expression. The selective induction of TIMP-1 by OM may be influential in altering matrix destruction in chronic inflammation and tumor metastasis.
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PMID:Selective regulation of metalloproteinase inhibitor (TIMP-1) by oncostatin M in fibroblasts in culture. 851 78

For the propose of detecting the significance of stromelysin (of matrix metalloproteinase family) mRNA expression in the invasion and metastasis process of liver cell carcinoma, 19 cases of human hepatocellular carcinoma (HCC) and their surrounding tissues were studied by in situ hybridization techniques. Nine cases of the HCC tissues were positive while all the tumor surrounding tissues were negative. The stromelysin expression levels were higher in those HCC complicated with portal tumor emboli or in those classified pathologically in II-IV degree. It is considered that portal cancer emboli is a characteristic event for intrahepatic and extrahepatic metastasis of HCC, and matrix metalloproteinase may be of importance for the tumor invasion and metastasis.
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PMID:[Detection of stromelysin mRNA expression in human hepatocellular carcinoma by in situ hybridization]. 920 7

To analyze matrix metalloproteinase (MMP) mRNAs that are expressed in hepatocellular carcinoma cell lines, the kinds of MMP mRNAs were surveyed in HepG2 and Hep3B cells and normal liver by a reverse transcription-polymerase chain reaction using two degenerate primer pairs, derived from conserved domains of known MMPs. The level for each MMP mRNA was examined by Northern blot analysis in HepG2 and Hep3B cells, as well as in normal tissues. It was also examined by a reverse transcription-polymerase chain reaction analysis in 8 different hepatocellular carcinoma cell lines. MMP-2, MMP-14, and MMP-15 mRNAs were expressed at elevated levels in most of the cell lines studied, reflecting that these MMPs would play an important role in the invasion and metastasis of hepatocellular carcinoma. MMP-1, MMP-3, MMP-8, MMP-10, MMP-11, and MMP-13 mRNAs were also expressed in some or most of the cell lines. Interestingly, MMP-9 mRNA, as well as its polypeptide, was undetected in all of the cell lines studied. This implies that MMP-9, which was suggested as a tumor marker for hepatocellular carcinoma, would be expressed in stromal cells, rather than tumor cells. These results provide information for the basal levels of MMP mRNAs in various hepatocellular carcinoma cell lines. It will also facilitate study on the transcriptional regulation of each MMP mRNA by oncogenes.
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PMID:Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. 1156 28

Intra-hepatic invasion is a key feature of hepatocellular carcinoma (HCC) progression. We have shown that human liver myofibroblasts induce invasion of HCC cells through Matrigel, via the secretion of hepatocyte growth factor (HGF). In our study, we investigated the role of matrix metalloproteinases (MMP) in HGF-induced HCC cells invasion. Marimastat, a synthetic MMP inhibitor, dose-dependently decreased HGF-induced invasion of HepG2 cells with a maximum of 82.7 +/- 13.3% at 20 microM. TIMP-2, a natural inhibitor, decreased invasion up to 51.2 +/- 11.2% at 200 ng/ml. To determine the target for these inhibitors, we examined MMP expression using RT-PCR. MMPs 1, 7-9 and 10 were not expressed in HepG2 cells either in the absence or in the presence of HGF. MMP-2 and MMP-13 transcripts were detected in unstimulated cells but their expression was unchanged after exposition to HGF. MMP-3 transcripts were undetectable in unstimulated HepG2 cells. They became clearly expressed in HGF-stimulated cells, however, and this was confirmed by Northern blot. By Western blot, HGF dose-dependently stimulated the secretion of pro-MMP-3 in the culture medium. The role of MMP-3 in HGF-induced invasion was directly confirmed by using an antibody to MMP-3, that blocked invasion. Finally, RT-PCR demonstrated MMP-3 expression in 10/16 human HCCs tested, but not in normal liver. In conclusion, our data demonstrate that MMPs, most likely MMP-3, mediate HGF-induced invasion of HCC cells. The in vivo expression of MMP-3 in HCC suggests a role for this protease in HCC progression.
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PMID:Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. 1177 58

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

Matrix metalloproteinases (MMPs) specially degrade extracellular matrix (ECM) proteins and are involved in tissue remodeling and angiogenesis. Therefore, studies on the role of MMPs in the carcinogenesis, proliferation and infiltration of hepatocellular carcinoma (HCC) may greatly contribute to the development of a new clinically applicable therapeutic approach. In the present study, we immunologically examined the expression rates of various MMPs including MMP-2, 3, 7, 9, membrane type 1-MMP (MT1-MMP), and MT2-MMP in the cancerous and noncancerous areas of resected tumor specimens from 30 patients with primary HCC. The rate of MMP-2 expression was high for both cancerous and noncancerous areas. However, the expression rates of MMP-3, MT1-MMP, and MT2-MMP were significantly higher in cancerous areas than in noncancerous areas. Next, we examined the clinicopathologic features such as the number of tumor nodules, maximal tumor size, presence or absence of capsular infiltration and portal vein invasion, histological grades of HCCs, state of noncancerous areas (chronic hepatitis: CH or liver cirrhosis: LC), and short-term recurrence after resection (within six months). In conclusion, it was found that three main networks of MMPs are predominantly involved in the case of HCC, that is, MMP-2 and MT1-MMP in the carcinogenesis and progression, MMP-7 and MMP-9 in the capsular infiltration and portal vein invasion, as well as MMP-3 and MMP-7 in the progression of HCC. Furthermore, MT1-MMP appeared to be the most important factor in HCC because of its widespread pattern of expression.
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PMID:A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma. 1458 7

Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) catalyzes the isomerization between glucose-6-phosphate and fructose-6-phosphate, and is involved in cytokine activity, mitogenesis, differentiation, oncogenesis, and tumor metastasis. Presently, we demonstrate that exogenous PGI/AMF stimulates the migration of Huh7 and HepG2 hepatoma cells, but not Hep3B cells. Inhibition of PGI/AMF by PGI/AMF specific inhibitor 5-phospho-D-arabinonate markedly repressed the cellular migration. RT-PCR was used to examine the expression profile of matrix metalloproteinases (MMPs). MMP-3 transcripts, protein level, and secreted form were significantly upregulated in PGI/AMF-treated Huh7 and HepG2 cells, but not in Hep3B cells. MMP-3 inhibition abolished the PGI/AMF-induced cell motility. The observations are consistent with a downstream mediation role of MMP-3 in PGI/AMF-stimulated tumor cell metastasis.
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PMID:Induction of hepatoma cells migration by phosphoglucose isomerase/autocrine motility factor through the upregulation of matrix metalloproteinase-3. 1471 48


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