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)

Invasion and metastasis requires a series of interactions between malignant cells and the extracellular matrix (ECM). Antigen markers that relate to these interactions were evaluated for prognostic correlation in human hepatocellular carcinoma. Basement membrane type IV collagen (cIV), type IV collagenase (cIVase), laminin, and laminin receptors (LRs)--all ECM antigens previously proposed to be modulated in association with tumor aggressiveness--were immunohistochemically investigated in 30 cases of hepatocellular carcinomas (HCCs). The pattern of antigen expression was correlated with 1) 36 months' clinical follow-up and 2) the pathologic grade. As a means of estimating the proliferation fraction, an additional antigen, Ki67, was also studied in this series. There were major differences in the distribution of cIV and laminin, and in the quantity of cIVase-, LR-, and Ki67-positive cells associated with grade and prognosis. A smaller quantity of cIV and laminin and a higher number of cIVase-, LR-, and Ki67-positive cells were detected in the poorly differentiated compared with the well-differentiated HCCs. The tumors with lower immunoreactivity for cIV and laminin components accompanied by a higher number of cIVase-, LR-, and Ki67-positive cells fall into a group with the poorest overall survival (P less than 0.006). The panel of antigens is proposed as a useful prognostic tool for evaluating HCC tumor aggressiveness.
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PMID:Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens. 184 41

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

A one-step sandwich enzyme immunoassay (EIA) for human matrix metalloproteinase 2 (MMP-2, 72-kDa gelatinase/type IV collagenase, EC 3.4.24.24) was established with a pair of monoclonal antibodies prepared against the precursor form of MMP-2 (proMMP-2) purified from the conditioned medium of human skin fibroblasts or against a synthetic peptide corresponding to the N-terminal domain of proMMP-2. ProMMP-2 in samples was allowed to simultaneously react with both solid-phase and peroxidase-labeled antibodies. Sensitivity of this EIA system was 2.4 pg/assay (0.24 microgram/l) and linearity was obtained between 10 and 5,000 pg/assay (1.0-500 micrograms/l). The EIA system recognized both the free form of proMMP-2 and its complex form with TIMP-2 with the same degree of immunoreactivity. ProMMP-2 levels in human sera from patients in various disease states were analyzed. In sera from patients with hyperthyroidism (12), primary biliary cirrhosis (8) and hepatocellular carcinoma (11), 749 +/- 166, 716 +/- 135 and 686 +/- 236 micrograms/l of proMMP-2 were detected, respectively and these were significantly higher than that observed in 213 normal human sera (570 +/- 118 micrograms/l). In contrast, the levels in sera from 33 patients with osteoarthritis (449 +/- 72 micrograms/l), 45 with rheumatoid arthritis (408 +/- 139 micrograms/l), 13 with stomach cancer (427 +/- 103 micrograms/l) and 10 with pancreatic cancer (422 +/- 130 micrograms/l) were significantly lower than that found in normal sera. Immunoblot and gel filtration analyses showed that human sera contain several MMP-2 species in addition to proMMP-2 which exist in a complex form with TIMP-2.
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PMID:A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 2 (72-kDa gelatinase/type IV collagenase) using monoclonal antibodies. 814 45

A one-step sandwich enzyme immunoassay system was developed with a pair of monoclonal antibodies against two individual oligopeptides prepared from the amino acid sequence of the human tissue inhibitor of metalloproteinases-2 (TIMP-2). The assay system consisting of two simultaneous immunoreactions used a solid phase monoclonal antibody and a horse-radish peroxidase-labeled monoclonal antibody. The system detected a free form of TIMP-2 and that complexed with active forms of matrix metalloproteinases (MMPs) giving a different sensitivity for each MMP but not TIMP-2 complexed with the precursor of 72 kDa gelatinase/type IV collagenase (MMP-2). The sensitivity of the system was 1.6 microgram/l (16 pg/assay) and linearity was obtained between 6.3 and 50 micrograms/l (63-500 pg/assay). TIMP-2 levels in the sera of 20 patients with rheumatoid arthritis (68 +/- 25 micrograms/l, mean +/- S.D.) and 13 patients with hepatocellular carcinoma (76 +/- 46 micrograms/l) were significantly higher (P < 0.05) than those of 18 normal subjects (5.6 +/- 7.4 micrograms/l). In contrast, the levels in the sera of 10 patients with gastric cancer (45 +/- 18 micrograms/l) and 7 patients with cancer of the uterus (36 +/- 13 micrograms/l) were significantly lower (P < 0.05 or P < 0.01) than those of normal subjects. Immunoreactivity analyses suggested that the precursor of MMP-2 in normal sera exists in a complexed form with TIMP-2 by interacting with the C-terminal domain of TIMP-2.
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PMID:A one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases-2 using monoclonal antibodies. 828 59

The assessment of biological markers as potential indicators of disease aggressiveness is still an open problem in hepatocellular carcinoma. Cell proliferation and extracellular matrix (ECM)-associated antigens and tumor-cell products can be associated with clinical aggressiveness in this tumor type, as has already been demonstrated for others. Cell proliferation, expressed as the in vitro [3H]thymidine labeling index, and ECM-associated antigens, such as type IV collagenase and laminin receptors, were assessed on the same paraffin-embedded samples. A strong association (P = 0.0001) was observed between the expression of collagenase and laminin receptors, with a correlation coefficient (rs) of 0.68. No relationship was found between cell proliferation and ECM-associated antigens. Moreover, the biological markers were generally independent of clinicopathologic features, except for a higher number of collagenase- and laminin receptor-positive cells in large (> or = 5 cm) compared with small (< 5 cm) tumors. In the present series of hepatocellular carcinoma patients, the 3-year clinical outcome was significantly affected by cell proliferation and ECM-associated antigens.
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PMID:Biological markers in hepatocellular carcinoma: potential clinical implications. 838 67

The matrix metalloproteinase gelatinase A plays a central role in several critical physiologic processes, including angiogenesis, tumor invasion/metastasis, and chronic inflammation. We demonstrate that high level gelatinase A expression is mediated by a unique interaction of two developmentally regulated transcription factors, AP2 and YB-1, within a discrete 40-base pair enhancer element (RE-1) located in the 5'-flanking region of the gelatinase A gene. Electrophoretic mobility shift assay studies and immunoprecipitation experiments confirmed a direct interaction of AP2 with this binding sequence in the form of AP2.YB-1 heteromeric complexes. Binding of AP2.YB-1 complexes to the RE-1 sequence results in the formation of extended single-stranded DNA regions and may stabilize DNA conformational changes. Overexpression of YB-1 and AP2 proteins by gelatinase A synthesizing hepatoma HepG2 cells induced a synergistic increase in the RE-1-mediated transcription of nearly 160-fold. Thus, the transcription of gelatinase A is subject to a previously unrecognized interplay of double (AP2) and single-stranded (YB-1) DNA binding transcription factors to yield a highly regulated pattern of gene expression.
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PMID:A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription. 983 47

Destruction of the extracellular matrices is required for tumor invasion and metastasis. Matrix metalloproteinase-2 degrades type IV collagen and laminin, major components of the basement membrane. Membrane type 1 matrix metalloproteinase activates the latent form of matrix metalloproteinase-2. We studied changes in membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 expression in relation to the tumor differentiation of hepatocellular carcinomas. Activity of matrix metalloproteinase-2 was also evaluated in hepatocellular carcinomas and noncancerous tissues. Overall, 37 hepatocellular carcinomas were studied. Expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was determined by either immunohistochemistry (n=37) or in situ hybridization (n=6). Changes in membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 expression were evaluated in relation to tumor differentiation. Gelatinolytic activities were analyzed by gelatin zymography (n=4). Membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 were detected in hepatoma cells and stromal cells. In addition, these matrix metalloproteinases were detected in the same hepatoma cells. Increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was associated with tumor dedifferentiation. The active form of matrix metalloproteinase-2 was more strongly expressed by hepatocellular carcinomas than by noncancerous tissues. These findings indicate that increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 was associated with tumor dedifferentiation, suggesting that these matrix metalloproteinases are intimately involved in the invasion of hepatocellular carcinomas.
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PMID:Increased expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 with tumor dedifferentiation in hepatocellular carcinomas. 1020 54

Hepatocellular carcinoma (HCC) is the main type of primary liver cancer, and it develops from hepatocytes. The stroma of HCC is infiltrated by myofibroblasts. In other settings, such as liver fibrosis, myofibroblasts are derived mainly from the activation of hepatic stellate cells (HSC). In this study, we investigated whether tumoral hepatocytes were able to activate HSC. HSC were isolated from normal rats and were plated in dishes coated with Matrigel, to prevent their spontaneous activation. HSC were exposed to conditioned medium (CM) from the rat HCC lines Fao and H5. Tumor cell CM elicited major morphologic changes, such as spreading and generation of cytoplasmic processes. Fao and H5 CM increased HSC proliferation to 1.60 and 1.76 times control values, respectively. The expression of alpha-smooth muscle actin was low or undetectable in control cells and was markedly increased by both tumor cell CM but not by normal rat hepatocyte CM. Desmin expression was also enhanced. Gelatinase A secretion was significantly increased 1.20-fold by Fao CM and 1.55-fold by H5 CM. Expression of beta-type platelet-derived growth factor receptor mRNA was increased 5.8-fold by H5 CM but was decreased to 13% of control levels by Fao CM. HSC activation by tumor cell CM was not prevented by urokinase or matrix metalloproteinase inhibitors, suggesting that Matrigel degradation was not central to the activation process. Finally, a blocking antibody to transforming growth factor-beta1 did not impede Fao CM-induced activation but significantly blocked the increase in matrix metalloproteinase-2 expression induced by H5 CM. Our results show that tumoral rat hepatocyte CM is able to induce the activation of rat HSC in culture. The lack of induction of beta-type platelet-derived growth factor receptor mRNA by Fao CM indicates that, in some cases, tumor-induced activation differs from classic fibrosis-type activation. Our data thus suggest that HSC recruitment and activation in HCC could be under the control of tumor cells.
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PMID:Activation of cultured rat hepatic stellate cells by tumoral hepatocytes. 1021 1

Gelatinase A, also denoted matrix metalloproteinase 2, plays multiple critical roles in the neoplastic process, including facilitation of neoangiogenesis and formation of distal metastases. The transcriptional regulation of the gelatinase A gene is under the control of strong, evolutionarily conserved cis-acting enhancer elements, designated the r2 (human) or RE-1 (rat), that harbor contiguous binding motifs for the transcription factors activating protein-2 (AP2), p53, and YB-1. Using recombinant transcription factors, complex patterns of RE-1 binding were observed by electrophoretic mobility shift assay. Increased complex formation was detected with the AP2/YB-1 and AP2/p53 combinations, while YB-1 competed with p53 for binding. The combination of AP2, p53, and YB-1 yielded novel ternary complexes, particularly when binding to single-stranded RE-1 probes. Transient transfection of hepatocellular carcinoma cell lines with a series of gelatinase A luciferase reporter constructs were in accordance with the binding patterns determined by electrophoretic mobility shift assay. Combined AP2 and p53 increased gelatinase A luciferase reporter activity significantly, and the inclusion of YB-1 yielded further increase in both reporter activity and secreted levels of gelatinase A protein. YB-1 and p53 expression are increased following multiple genotoxic stresses, including irradiation, and the synergistic interactions of these induced transcription factors with the widely expressed AP2 protein provide a probable pathophysiologic mechanism for the enhanced tumor cell synthesis of gelatinase A induced by radiation.
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PMID:Combinatorial interactions of p53, activating protein-2, and YB-1 with a single enhancer element regulate gelatinase A expression in neoplastic cells. 1197 33

Halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of collagen alpha 1 (I) and matrix metalloproteinase 2 gene expression. Halofuginone also suppresses extracellular matrix deposition and fibroblast proliferation. It was recently shown to be effective in suppression of bladder carcinoma and glioma. This study sought to evaluate the effect of treatment with halofuginone on growth of hepatocellular carcinoma (HCC) in mice. Athymic Balb/c mice were injected subcutaneously with 10(7) human hepatoma cells (Hep3B), followed by treatment with halofuginone administered in the diet (750 microg/kg) starting on day 3, before tumour innoculation. The control group was received a normal diet. Mice were followed for survival, tumour volume and serum alpha-fetoprotein (alpha FP). The mechanism of the anti-tumour effect of halofuginone was determined in vitro by assessing tumour cell growth, and by measuring the serum concentrations of interferon-gamma (IFN gamma) and interleukin 2 (IL2). Halofuginone treatment induced almost complete tumour suppression in treated mice. Mortality rates were 10% and 50%, in halofuginone-treated and control mice, respectively (P<0.001). No visible tumour was observed in treated mice, as compared with a 364 mm3 tumour in control mice. Serum alpha FP were 0.1 and 212 ng/ml in treated and control mice, respectively (P<0.005). Halofuginone significantly inhibited HCC proliferation in vitro. Maximal inhibition of 64% of tumour cell growth was observed at a concentration of 10(-8) M. The anti-tumour effect was mediated via a significant increase in IFN gamma and IL2 (90 vs. 35, and 210 vs. 34 pg/ml in treated and control groups, respectively, P<0.005). Treatment with halofuginone effectively suppressed the progression of HCC in mice. This effect may be associated with a direct anti-tumour effect, and/or enhancement of a systemic immune response.
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PMID:Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone. 1517 99


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