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

Treatment of rodent cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate activates protein kinase C, leading to increased expression of several genes, including a gene originally designated TPA-S1 or phorbin (M. D. Johnson, G. M. Housey, P. T. Kirschmeier, and I. B. Weinstein, Mol. Cell Biol., 7: 2821-2829, 1987). Sequence analysis of this cloned gene indicated homology with human erythroid-potentiating activity and tissue inhibitor of metalloproteinase (TIMP-1). Elevated levels of phorbin mRNA have been observed in human colon tumors (J. G. Guillem, M. F. Levey, L. L. Hsieh, M. D. Johnson, P. LoGerfo, K. A. Forde, and I. B. Weinstein, Mol. Carcinogen., 3: 68-74, 1990) and this increase correlated with the extent of invasion. To further investigate this phenomenon at the protein level, monoclonal antibodies were developed against the recombinant form of TIMP-1. A competitive enzyme-linked immunosorbent assay was developed for quantitation of the TIMP-1 protein in tissue extracts. Elevated levels of TIMP-1 protein were found in 31 human colon tumors, compared to paired samples of adjacent normal mucosa. In a subset of samples, previously analyzed for phorbin mRNA levels (n = 25), there was a good correlation between the abundance of TIMP-1 protein and phorbin mRNA. Immunoaffinity column purification of tumor extracts followed by Western blot analysis was used to confirm the enzyme-linked immunosorbent assay data. These results provide evidence that phorbin and TIMP-1 represent the same gene. In addition, the immunoassays we have developed may be useful in further studies on the role of TIMP-1 in human colon cancer.
 ...
PMID:Immunological quantitation of levels of tissue inhibitor of metalloproteinase-1 in human colon cancer. 193 83

nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor beta 1 (TGF beta 1) signal transduction. In an earlier study we decreased nm23 mRNA levels 2- to 8-fold by antisense phosphorothiolated oligonucleotides in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGF beta 1. Only TGF beta 1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility. HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23 mRNA levels, while HD3 cell motility was conversely decreased by TGF beta 1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGF beta 1 or TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGF beta 1 and 5-fold by TGF alpha, but not by scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of proteases or modulation of their levels by TGF beta 1. Both HD3 and U9 cells displayed equal levels of urokinase activity and mRNA, equal expression of the metalloproteinase inhibitor TIMP-1, and no detectable collagenases by zymography. No differential response to TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.
 ...
PMID:Colon carcinoma cells with inactive nm23 show increased motility and response to motility factors. 755 87

We have previously reported that human colon cancer cells secrete a factor(s) which induces elongation of colon fibroblasts in vitro. Isolation of this factor led to the identification of a 55kD protein with fibroblast stretching activity. Two internal amino acid sequences identified in this protein (YEI; GFQALGDAADI) share complete homology with tissue inhibitor of metalloproteinase (TIMP-1).
 ...
PMID:A fibroblast elongation factor purified from colon carcinoma cells shares sequence identity with TIMP-1. 782 76

Recent epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in individuals who take nonsteroidal antiinflammatory drugs on a regular basis compared with those not taking these agents. One property shared by all of these drugs is their ability to inhibit cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. Human colon cancer cells (Caco-2) were permanently transfected with a COX-2 expression vector or the identical vector lacking the COX-2 insert. The Caco-2 cells, which constitutively expressed COX-2, acquired increased invasiveness compared with the parental Caco-2 cells or the vector transfected control cells. Biochemical changes associated with this phenotypic change included activation of metalloproteinase-2 and increased RNA levels for the membrane-type metalloproteinase. Increased invasiveness and prostaglandin production were reversed by treatment with sulindac sulfide, a known COX inhibitor. These studies demonstrate that constitutive expression of COX-2 can lead to phenotypic changes that alter the metastatic potential of colorectal cancer cells.
 ...
PMID:Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. 909 94

A novel mRNA isoform encoding the cell surface metalloproteinase meprin beta is expressed in mouse teratocarcinoma cells and in a variety of cultured human cancer cells. In both mouse and human cells, the cancer cell-specific mRNA isoform, referred to as beta', has an extended 5' UTR as compared to the meprin beta mRNA isoform expressed in normal kidney and intestinal epithelium. The work herein aimed to determine the molecular mechanisms for the expression of meprin beta and beta' in normal and cancer cells, respectively. Analysis of the 5' end of the mouse meprin beta gene revealed that the unique sequences in the beta and beta' mRNA isoforms are encoded by separate exons that are alternately spliced, and transcribed from independent promoters. By contrast, the human meprin beta and beta' mRNAs have identical sequences except for 87 additional bases in the 5' UTR sequence of beta', indicating that a single, mixed usage promoter directs expression of the isoforms. The region upstream of the human meprin beta' transcription start site contained elements with homology to the promoters of intestine-specific genes, interspersed with AP-1 and PEA3 elements; the latter were essential to meprin beta' promoter activity in cancer cells. Phorbol myristal acetate increased meprin beta' mRNA levels in cultured human colon cancer cells, providing further evidence that AP-1/PEA3 sites are actively involved in meprin beta' expression.
 ...
PMID:Meprin B: transcriptional and posttranscriptional regulation of the meprin beta metalloproteinase subunit in human and mouse cancer cells. 1019 Feb 76

Phorbol esters such as phorbol 12-myristate 13-acetate (PMA) have been reported to modulate diverse cellular responses through signal transduction pathways including the protein kinase C (PKC) pathway. In the present study, we sought to determine the effect of PMA on mucin gene expression and on the biological properties of a human colon cancer cell line, HM3. The cells were treated for 8 and 24 h with various concentrations of PMA and total RNA was extracted and Northern and slot blot analyses were carried out using MUC2, MUC3 and MUC5AC mucin cDNA probes to assess the steady state levels of mRNA. Spent media were collected and the level of cancer associated carbohydrate antigens (T, Tn, sialyl Tn, sialyl Lex, and sialyl Lea) and matrix-degrading metalloproteinase (MMPs) activity were examined. Trypsinized cells were used for assessing in vitro invasion, motility and adhesion to matrigel. Our results showed that PMA caused upregulation of steady state mRNA levels of MUC2, MUC3 and MUC5AC which was inhibited after treatment with protein synthesis inhibitors. Calphostin C, a highly specific inhibitor of protein kinase C significantly inhibited the PMA induced induction of mRNA levels of MUC2, MUC3, and MUC5AC. The levels of all cancer-associated mucin carbohydrate antigens examined in the media were increased by PMA treatment. PMA also caused an increase in MMPs activity and in in vitro invasion and motility properties, but did not affect adhesion of HM3 cells to matrigel. Thus, PMA caused a significant increase in the expression of all three mucin genes through signaling pathways involving protein kinase C and increased secretion of mucin associated carbohydrate antigens. These changes were associated with increases in MMP activity as well as by increases in the invasive and motility properties of HM3 colon cancer cells. These data suggest that protein kinase C signaling pathways may be involved in mucin gene regulation and in modulating the invasive and metastatic properties of colon cancer cells.
 ...
PMID:Phorbol 12-myristate 13-acetate induces alteration in mucin gene expression and biological properties of colon cancer cells. 1093 88

TIMP-2 is a natural matrix metalloproteinase (MMP) inhibitor that prevents the degradation of extracellular matrix proteins. It abolishes the hydrolytic activity of all activated members of the metalloproteinase family and in particular that of MT1-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis. Since MMPs have been implicated in both cancer progression and angiogenesis, we generated a recombinant adenovirus to deliver human TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 inhibited the invasion of both tumor and endothelial cells without affecting cell proliferation. Its in vivo efficiency has been evaluated in murine lung cancer LLC, and colon cancer C51 in syngeneic mice as well as in human breast cancer MDA-MB231 in athymic mice. Preinfection of tumor cells by AdTIMP-2 resulted in an inhibition of tumor establishment in more than 50% of mice in LLC and C51 models and in 100% mice in the MDA-MB231 model. A single local injection of AdTIMP-2 into preestablished tumors of these three types significantly reduced tumor growth rates by 60--80% and tumor-associated angiogenesis index by 25--75%. Lung metastasis of LLC tumor was inhibited by >90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged survival in all the cancer models tested. These data demonstrate the potential of adenovirus-mediated TIMP-2 therapy in cancer treatment.
 ...
PMID:AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. 1126 84

The differential expression of hundreds of tightly, transcriptionally controlled genes in isolated human colorectal cancer and respective normal mucosa from two patients was analyzed by the cDNA macroarray technique. mRNA prepared from the colorectal cancer tumors was compared with 588 genes spotted onto the filter. Case A showed down-regulation of the expression of cell-cycle-related genes including cyclins, cyclin-dependent kinase (CDK) 2, and CDK-activating kinase, as compared with normal mucosa from the same patient. The tumors showed up-regulation of expression of angiogenesis-related genes such as type II cytoskeletal 8 keratin, metalloproteinase subtypes, VEGF, and bFGF, to over 5-fold the levels in normal mucosa. Thus, colorectal carcinoma tissues are characterized by the upregulation of molecules related with angiogenesis. These results suggest that angiogenesis-related molecules are suitable candidates for target-based therapies for colorectal cancer patients. In case B, the largest difference in expression between the tumor and mucosal tissues was observed in the MMP-1 gene. In contrast to the first case, there was no increase in expression of angiogenesis-related molecules or decrease in expression of cell-cycle-regulatory molecules. The expression profile was quite different between these two patients. This approach may eventually provide a mean of selecting target-based drugs in individual colon cancer patients.
 ...
PMID:Upregulated expression of angiogenesis genes and down regulation of cell cycle genes in human colorectal cancer tissue determined by cDNA macroarray. 1129 27

Matrix metalloproteinase-2 (MMP-2) is overexpressed in human cancers and facilitates tumor growth and metastasis. It is synthesized as an inactive proenzyme that is activated by membrane-type matrix metalloproteinase-1 (MT1-MMP) and inhibited by tissue inhibitor of metalloproteinase-2 (TIMP-2). We hypothesized that there is an imbalance between the expression of TIMP-2 and the expression of MMP-2 and MT1-MMP that favors activation of MMP-2 in malignant colon tumors compared to normal colonic tissue. Specimens of colon tumors and of adjacent normal mucosa were obtained from 22 patients at the time of surgical resection. MMP-2, MT1-MMP, and TIMP-2 RNA transcripts were measured in each sample using a quantitative reverse transcriptase polymerase chain reaction assay. We observed that MMP-2 RNA levels were significantly elevated in tumors compared to normal tissue (P = 0.039). In addition, the TIMP-2:MMP-2 ratio was twofold lower (P = 0.001) and the TIMP-2:MT1-MMP ratio was 1.5-fold lower (P = 0.003) in tumors compared to normal mucosa. These results suggest that the balance between genes that activate and inhibit MMP-2 is shifted toward activation in colon tumors. The abnormal expression of gene products that regulate MMP-2 activity may be an important early step in the malignant transformation of colon cancer and may provide a useful target for new chemoprevention and adjuvant treatment strategies.
 ...
PMID:Balance between activation and inhibition of matrix metalloproteinase-2 (MMP-2) is altered in colorectal tumors compared to normal colonic epithelium. 1218 36

Expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) strongly correlates with a malignant tumour cell phenotype. In the multistep process of metastasis, uPA binding to uPAR influences different cellular functions. In the present study, a highly metastatic colon cancer cell line, HCT116 was transfected with an expression vector containing a 5' uPAR cDNA fragment in an antisense orientation. This construct was most effective in reducing uPAR cell surface expression as confirmed by flow cytometry analysis. Antisense transfection of HCT116 cells had no effect on proliferation but the following effects were observed: (1) a 1.3-fold decreased adhesion; (2) a two-fold decreased Erk MAP kinase activity; (3) a 2.7-fold decrease in Src kinase activity; (4) a 1.5- and two-fold decrease in uPA cell surface expression and secretion; (5) abrogation of promatrix metalloproteinase-9 secretion; and (6) a complete suppression of plasminogen-dependent matrix degradation. Using proteomic analysis, we demonstrate loss of approximately 200 proteins and quantitative differences in the expression of 141 other proteins in an antisense-clone compared to wild-type and mock-transfected control. Such changes in protein expression with the down-regulation of uPAR may be an important contributor in colon cancer progression and metastasis and may not only provide a basis to develop a proteomic data bank of uPAR-mediated signaling molecules but may also lead to the development of therapeutic approaches for the cure and better management of colon cancer.
 ...
PMID:Proteomic profiling of proteins associated with urokinase plasminogen activator receptor in a colon cancer cell line using an antisense approach. 1262 82


1 2 3 4 5 Next >>