Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cDNA (DPCR1) specific for human intestinal dipeptidyl peptidase IV (DPP IV) has been isolated. This 1.7-kilobase cDNA, together with a previously published partial sequence, covers the entire open reading frame of human DPP IV plus 67 base pairs of the 3'-untranslated end. Human DPP IV is a 766-amino acid polypeptide with a high degree of homology with the rat liver protein. The characterization of this molecular probe allowed us to definitively confirm the identity of DPP IV with CD 26, a mouse thymocyte activation antigen, a conclusion strengthened by the fact that we observed identical patterns on Southern blot of human genomic DNA hybridized either with human DPP IV or mouse CD 26 cDNA probe. Using this new tool, we have investigated the expression of DPP IV during the onset of enterocytic differentiation of two cultured human colon cancer cell lines, HT-29 and Caco-2. Whatever the cell line and the culture conditions, DPP IV expression strictly correlates with the presence of a differentiated phenotype, as shown by enzyme activity and the steady state amount of the protein measured by indirect immunofluorescence and Western blot. Accordingly, DPP IV biosynthesis exclusively increases in cells that display an enterocytic differentiation. Neither the glycosylation nor the stability of the protein appear to be dependent on the state of enterocytic differentiation. The DPP IV mRNA level remains very low in undifferentiated cell populations and specifically increases in cells that undergo an enterocytic differentiation. These results strongly suggest that DPP IV gene expression is controlled at the transcriptional or posttranscriptional level during intestinal differentiation.
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PMID:Dipeptidyl peptidase IV (CD 26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2. Cloning of the complete human coding sequence and changes of dipeptidyl peptidase IV mRNA levels during cell differentiation. 134 43

Staurosporin, a broad-spectrum kinase inhibitor, induced cell spreading in a human colon cancer cell line, Colo 201. On collagen and laminin, cell spreading was induced in more than 90% of the cells and was dependent on very late activation antigen-3, as shown by an antibody inhibition assay. Cell spreading required divalent cations and showed the order of preference Mn2+ > Mg2+ > Ca2+. On fibronectin, only about 30% of the cells were observed to spread, and spreading occurred via a non-integrin, RGD-independent pathway. Staurosporin-induced spreading was inhibited by treatment with tyrosine kinase inhibitors herbimycin A and methyl 2,5-dihydroxycinnamate. Despite the presence of staurosporin, seven proteins (220, 175, 150, 98, 62, 58, and 45 kDa) showed increased levels of tyrosine phosphorylation in association with cell adhesion. Two of these (58 and 220 kDa) were identified by immunoprecipitation as Src product and tensin, respectively. Flow cytometric analysis showed that the Colo 201 cells expressed the alpha 2, alpha 3, alpha 6, and beta 1 chains of integrin, but expression of these chains was not influenced by staurosporin. Immunofluorescence microscopy revealed that the alpha 3 chain, diffusely expressed on the cell surface in the absence of staurosporin, was concentrated at focal adhesion plaques after staurosporin treatment. Neither alpha 2 nor alpha 6 was focalized by the treatment.
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PMID:Cell spreading in Colo 201 by staurosporin is alpha 3 beta 1 integrin-mediated with tyrosine phosphorylation of Src and tensin. 753 Jul 22

The host reaction is an important factor in the biological behavior of cancers. In human colon adenocarcinoma, stromal cells and some cancer cells express the urokinase receptor (uPAR), a molecule involved in the regulation of extracellular proteolysis. The present study reveals the identity of uPAR-expressing cell types and the subcellular localization of this molecule by immunoelectron microscopy in colon cancer. uPAR-positive cells were most abundant at the invasive margin of colon cancer and were identified as macrophages, fibroblasts, neutrophilic and eosinophilic granulocytes, endothelial cells and cancer cells. Of these, the most numerous were macrophages with uPAR detected along the plasma membrane, in accordance with its function in plasminogen activation on the cell surface. Fibroblasts were labeled in the lumen of rough endoplasmic reticulum, indicating its intracellular synthesis. Some granulocytes and endothelial cells expressed immunoreactivity along the plasma membrane. uPAR-positive cancer cells were stained along the plasma membrane and in rough endoplasmic reticulum. These findings suggested that a variety of non-malignant host cells play an important role in the plasmin-mediated breakdown of the extracellular matrix at the invasive margin.
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PMID:Expression of urokinase receptor in various stromal-cell populations in human colon cancer: immunoelectron microscopical analysis. 755 16

Recombinant human gamma 2 chain of laminin-5 was expressed in Escherichia coli, and used to generate specific polyclonal antibodies which were used to study the distribution of the protein in human cancers. A total of 72 biopsies of human cancers were stained, including 23 cases of colon adenocarcinomas, 16 ductal breast carcinomas, 9 malignant melanomas, 14 squamous cell carcinomas of the skin and cervix, and 10 sarcomas. As a control for the specificity of the antibodies, we performed in situ hybridization on adjacent sections of a number of the cases, and in all of these cases the localization of the gamma 2 chain protein and mRNA was identical. We found gamma 2 chain immunoreactivity in cancer cells in all cases of colon adenocarcinomas and squamous cell carcinomas but not in any of the sarcomas, supporting the view that the laminin-5 protein is specific for cells of epithelial origin. Notably, in all of the cases of colon adenocarcinomas, the positive staining was invariably associated with budding cancer cells located at the tip of invading malignant epithelium, whereas the cancer cells deeper in the tumors were most often negative. The staining was cytoplasmic in all cases and only in one case did we see additional extracellular immunoreactivity, indicating that this laminin isoform in cancer tissue is not laid down in the extracellular matrix but probably exerts its function at the cell surface or in its immediate vicinity. Using in situ hybridization to analyze the coexpression of laminin-5 and components of the plasminogen activation system, we found that the histological distribution of laminin-5-positive budding cancer cells at the invasion front in colon adenocarcinomas was identical to that of the receptor for urokinase-type plasminogen activator. These findings suggest that laminin-5 is a marker of invading cancer cells in at least some human malignancies, and that it therefore might represent a valuable marker for the invasive potential of these cancers. The colocalization of laminin-5 and urokinase-type plasminogen activator receptor in a subset of cancer cells in colon cancer also suggests that a controlled up-regulation of a number of gene products is a characteristic of budding colon cancer cells, and that these gene products serve functions crucial for the invasive phenotype of these cancer cells.
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PMID:Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. 766 91

The urokinase-type plasminogen activator receptor (u-PAR) facilitates extracellular matrix proteolysis by accelerating plasmin formation at the cell surface. The present study was undertaken to identify elements in the u-PAR promoter required for the elevated expression of this binding site. Toward this end, we used two cultured colon cancer cell lines; one (RKO) has a transcriptionally activated u-PAR gene, and the other (GEO) overexpresses the receptor only after phorbol ester treatment. A chloramphenicol acetyltransferase (CAT) reporter driven by 398 nucleotides of 5' regulatory sequence of the u-PAR gene was strongly activated in the RKO cells, which displays approximately 3 x 10(5) receptors/cell. A region of this promoter between -197 and -8 was required for optimal expression, as indicated using a CAT reporter driven by 5' deleted fragments. DNase I footprinting revealed three protected regions (I, -190 to -171; II, -148 to -124; and III, -99 to -70) in this part of the promoter. Mutation of an AP-1 binding site at -184 within region I reduced activation of the promoter by 85%. Deletion of either region II or III also reduced promoter activity by over 60%. An oligonucleotide spanning the AP-1 motif at -184 bound, specifically, nuclear factors from RKO cells, and antibodies specific for Jun-D, c-Jun, or Fra-1 proteins supershifted the complex indicating the presence of these proteins. The amount of these factors was reduced in GEO cells in which the u-PAR gene is only weakly transcriptionally activated. Expression of a vector encoding a wild-type Jun-D cDNA increased u-PAR promoter activity in GEO cells. Conversely, transfection of RKO cells with a transactivation domain-lacking Jun-D expression construct resulted in a dose-dependent decrease in u-PAR promoter activity. Treatment of GEO cells with phorbol ester increased u-PAR mRNA and the activity of a CAT reporter driven by the wild-type but not the AP-1 (-184)-mutated u-PAR promoter, and this was associated with a strong induction in the amount of Jun-D, c-Jun, and c-Fos. Methylation interference studies using a fragment of the u-PAR promoter (spanning -201 to -150) bound with nuclear extracted proteins from RKO cells, and phorbol 12-myristate 13-acetate-treated and -untreated GEO cells showed that the contact points corresponded to the AP-1 binding site at -184. Thus, the elevated expression of u-PAR in RKO cells, which constitutively produces this binding site, as well as in phorbol 12-myristate 13-acetate-stimulated GEO cells requires an AP-1 motif located 184 bp upstream of the transcriptional start site.
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PMID:Requirement of an upstream AP-1 motif for the constitutive and phorbol ester-inducible expression of the urokinase-type plasminogen activator receptor gene. 879 12

MMP-9 (gelatinase B) and urokinase-type plasminogen activator receptor (u-PAR), which are involved in cancer cell invasion and metastasis, are reported to be predominantly expressed by immune/inflammatory cells in human colorectal cancers. To investigate their significance in cancer progression, we morphometrically analyzed the tissue expression of MMP-9 and u-PAR among different stages of colorectal cancer. The numbers of MMP-9- and u-PAR-positive cells along the invasive margin were significantly smaller in cases with liver metastasis than in cases without liver metastasis, and were also smaller in cases with an infiltrating margin than in cases with an expanding margin. Both variables were larger in colon cancer cases with conspicuous lymphocytic infiltration. These results indicated that the degree of tissue expression of MMP-9 and u-PAR by host cells is inversely associated with liver metastasis and an infiltrating growth pattern in human colorectal cancers. Essentially the same results were obtained for the number of macrophages distributed along the invasive margin. We also found that the expression pattern of MMP-9 was similar to that of MMP-8 (polymorphonuclear leukocyte collagenase). These data are consistent with clinicopathologic studies of host cells. Therefore, our data suggest a dual role of MMP-9 and u-PAR expression in colon cancer tissue; i.e., not only are these proteinases cancer-promoting factors, but also they are related to the host defensive mechanism when they are expressed by host cells.
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PMID:Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. 904 99

The urokinase-type plasminogen activator receptor (u-PAR) facilitates extracellular matrix degradation in part by accelerating plasmin formation at the cell surface. We previously reported that u-PAR expression is elevated in colon cancer cell lines characterized by their in vitro invasive capacity. Since, u-PAR expression is increased by a variety of growth factors, which signal through the extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2), we determined if these mitogen-activated protein kinases (MAPKs) regulate u-PAR expression in two cultured colon cancer cell lines. An in-gel kinase assay showed that ERK1 activity was considerably higher in RKO cells, which display > or = 10(5) receptors/cell, than the GEO cells which have approximately 10(4) urokinase receptors per cell. The expression of either an ERK-inactivating phosphatase (CL100), or a kinase-defective ERK1, decreased the activity of a u-PAR promoter-driven CAT reporter in RKO cells. Immune complex kinase assays indicated that the constitutive ERK1 activity in RKO cells was largely a result of an activated MEK1. Further, treatment of RKO cells with a specific inhibitor (PD 098059) of MEK1 activation, which diminished ERK1 activity, reduced the amount of urokinase specifically bound to the cell surface and this was associated with reduced laminin degradation. The expression of a dominant negative c-Raf-1 also reduced u-PAR promoter activity suggesting that MEK1 activation involved an activator at, or upstream, of this serine-threonine kinase. Transfection of the u-PAR-deficient GEO cells with a constitutively activated MEK1 expression construct up-regulated u-PAR promoter activity. Similarly treatment of GEO cells with a phosphatase inhibitor (sodium vanadate) caused a dose-dependent increase in ERK1 activity which paralleled increased cell surface binding of urokinase. Taken together, these data suggest that elevated u-PAR expression, in at least a sub-population of colon cancer, is partly a consequence of a constitutively activated ERK-1-dependent signaling cascade.
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PMID:Elevated urokinase-type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade. 919 Oct 56

Measurement of urokinase receptor (uPAR) in tumor extracts has prognostic value, but assay of the soluble uPAR (suPAR) in peripheral blood may offer wider applications in cancer patient management. A tumor extract uPAR ELISA was modified to eliminate nonspecific plasma protein interference, enabling specific detection of suPAR in plasma and sera with >90% recovery of added calibrator. suPAR concentrations in citrate plasma correlated with sera in 93 healthy blood donors (r = 0.84, P <0.0001), with a median value for both of 1.2 microg/L. The plasma median for 19 advanced breast cancer patients was 2.9 microg/L suPAR, and a similar increase was found for 10 advanced colon cancer patients, consistent with release of suPAR from tumors into blood. Repetitive monitoring of suPAR in cancer patients' blood may have value in assessment of prognosis and tumor recurrence.
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PMID:ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. 934 6

An 8.5-kb 5'-flanking region of the human urokinase-type plasminogen activator receptor (uPAR) gene was cloned and the detailed uPAR promoter region defined in an 188-bp fragment between bases -141 and +47 relative to the transcription-start site. 5'-Deletion to -100 and -60 in the region abolished its promoter activity, indicating that an 81-bp segment between -141 and -61, which contains a proximal AP-1 site at position -70, is required for uPAR promoter activity. Nuclear extracts from HCT116 cells contain proteins that specifically bind to the AP-1 site. Mutation of the AP-1 motif reduced uPAR promoter activity in comparison with the wild-types. Induction of uPAR expression by phorbol ester requires this AP-1 motif in colon cancer cells. Cotransfection with the c-jun and c-fos expression vectors stimulated the uPAR promoter activity four- to fivefold. These results demonstrate that the proximal AP-1 motif is responsible for approximately 50% of the basal expression of the uPAR gene.
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PMID:A region between -141 and -61 bp containing a proximal AP-1 is essential for constitutive expression of urokinase-type plasminogen activator receptor. 1044 77

The role of urokinase-type plasminogen activator receptor (uPAR) in human colon cancer metastasis has not been tested using an antisense approach. In our study, the HCT116 cells, with high metastatic potential were transfected with expression vectors containing a 3' or 5' uPAR cDNA fragment in an antisense (AS) orientation. Transfection of 4 clones was confirmed by DNA hybridization analysis. Receptor-bound endogenous uPA activities of the clones were reduced to 16-68% of controls. The extracellular matrix degradation by the 4 clones was decreased to 33-76%. Two of the clones, 3'-AS7 and 5'-AS, were evaluated in an in vivo assay system of experimental metastasis using athymic mice. Pulmonary metastases were found in 63-78% mice injected with the parent HCT116 or control cells. In mice injected intravenously with the antisense transfected clones, 3'-AS7 and 5'-AS, however, pulmonary metastases were found in only 19% and 9% respectively (p < 0.05). These results provide direct evidence that both 3' and 5'-AS uPAR can inhibit colon cancer invasion and metastasis and may offer the prospect of defining specific targets for gene therapy.
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PMID:Inhibition of colon cancer metastasis by a 3'- end antisense urokinase receptor mRNA in a nude mouse model. 1129 Oct 54


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