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)

The matrix metalloproteinase matrilysin (MMP-7) is a member of the matrix metalloproteinase gene family, which is believed to play an important role in tumor invasion and metastasis. We have previously found that matrilysin mRNA is specifically expressed in colorectal cancers and adenomas and that its message is localized in the tumor cells themselves. We examined the effects of activated Ki-ras oncogene on the expression of matrilysin in colon cancer cells. We showed that both mRNA and the enzymatic activity of matrilysin were induced by the introduction of activated Ki-ras into SW1417 colon cancer cells. To understand the mechanisms regulating this induction, we analyzed alterations of AP-1 activity induced by activated Ki-ras, using the chloramphenicol acetyltransferase assay. AP-1 activity in SW1417 cells expressing activated Ki-ras was higher than that in control cells. The gel-shift assay also showed higher levels of AP-1 binding protein in SW1417 cells expressing activated Ki-ras than those in control cells. Our results suggest that activated Ki-ras may play a role in inducing expression of matrilysin through an AP-1-dependent pathway in colon cancer cells.
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PMID:Expression of matrix metalloproteinase matrilysin (MMP-7) was induced by activated Ki-ras via AP-1 activation in SW1417 colon cancer cells. 853 Oct 10

Human colon cancer frequently develops liver metastasis. Matrilysin (MMP-7), the smallest member of the matrix metalloproteinase (MMP) family, is commonly produced by human colon carcinoma cells and has been suggested to be involved in the progression and metastasis of this type of cancer. In the present study, we tested the effect of a matrilysin-specific antisense phosphorothioate oligonucleotide on liver metastasis of the human colon carcinoma cell line WiDr in nude mice. In culture, the antisense oligonucleotide moderately inhibited the secretion of matrilysin by WiDr cells. Injection of WiDr cells into the spleen of nude mice produced many metastatic tumor nodules in the liver. When the antisense oligonucleotide was injected daily into the mice for 11 days, the formation of the metastatic tumor nodules was strongly inhibited in a dose-dependent manner. An inhibition of liver metastasis of over 70% was obtained at a dose of 120 micrograms of the oligonucleotide per mouse. The antisense oligonucleotide did not inhibit tumor growth in spleen and in liver. A scrambled control oligonucleotide had no effect on liver metastasis of WiDr cells. Our results demonstrate an important role of matrilysin in liver metastasis of human colon cancer and the therapeutic potential of matrilysin antisense oligonucleotides for the prevention of metastasis.
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PMID:Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model. 962 46

Matrilysin (MMP-7) is the smallest member of the matrix metalloproteinase (MMP) family. It is frequently expressed in various types of cancer including colon, stomach, prostate, and brain cancers. Previous studies have suggested that matrilysin plays important roles in the progression and metastasis of colon cancer. Recently, we have examined the effects of a matrilysin-specific antisense phosphorothioate oligodeoxyribonucleotide on in vitro invasion and liver metastasis in nude mice of two human colon carcinoma cell lines (CaR-1 and WiDr). In culture, the antisense oligonucleotide effectively inhibited both the secretion of matrilysin by CaR-1 cells and their in vitro invasion through a reconstituted basement membrane. In a nude mouse model, the antisense oligonucleotide potently suppressed the experimental liver metastasis of WiDr cells from the spleen. These results suggest that matrilysin has an important role in the liver metastasis of human colon cancer and that matrilysin antisense oligonucleotides have therapeutic potential for the prevention of metastasis.
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PMID:Matrilysin as a target for chemotherapy for colon cancer: use of antisense oligonucleotides as antimetastatic agents. 1035 59

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

All-trans retinoic acid (ATRA), 9-cis retinoic acid and 13-cis retinoic acid are naturally occurring retinoids used in the prevention and therapy of various preneoplastic and neoplastic diseases. It was previously reported that matrilysin, one of the matrix metalloproteinases (MMP-7), plays a critical role in the invasion and metastasis of gastrointestinal cancers. Moreover, it has been shown that ATRA downregulates matrilysin expression and prevents in vitro invasion by colon cancer cells. In this study, three retinoids were used, both in Matrigel invasion assays and in subcutaneous xenografts in mice, to evaluate the effects of retinoids on invasion by colon cancer cell lines (CHC-Y1, DLD-1, HT-29, BM314, CaR-1 and WiDr). All three retinoic acids tested reduced matrilysin expression and suppressed the invasiveness of colon cancer cell lines in vitro. Retinoic acids also reduced tumor invasion in mice without influencing tumor growth. Matrilysin expression in these tumors was clearly reduced. These data support the use of retinoic acids as useful reagents to manage patients with colorectal carcinoma.
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PMID:Retinoic acids reduce matrilysin (matrix metalloproteinase 7) and inhibit tumor cell invasion in human colon cancer. 1139 50

Matrilysin, a member of matrix metalloproteinase family, is believed to play a significant role in the growth and proliferation of colon cancer cells. Overexpression of the matrilysin gene has been shown to correlate with Dukes' stage and increased metastatic potential in colorectal cancer. The aim of this study was to evaluate the effect of preoperative high-dose radiotherapy (25 Gy in five fractions over 5 days) on matrilysin (MMP-7) gene expression, in patients with resectable rectal cancer, by a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Biopsy samples of tumour (n=30) and distant normal mucosa (n=12) from 15 patients were obtained pre- and post-radiotherapy. Messenger (m)RNA was extracted from all of the tissue samples and reverse transcribed to double-stranded cDNA. Quantitative RT-PCR was performed to study the effect of preoperative radiotherapy on matrilysin gene expression in both the tumour and normal mucosal specimens. Matrilysin mRNA values were expressed relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for each sample. In 14 out of 15 cases, matrilysin mRNA was detected in the cancerous tissue. Although all six normal mucosal specimens expressed matrilysin mRNA, the levels were approximately 10-fold lower compared with those seen in the paired tumour samples. Preoperative radiotherapy led to a significant 6- to 7-fold increase (P=0.001) in the expression of matrilysin mRNA in rectal cancer tissue. In contrast, there was no significant change in the matrilysin mRNA expression of normal mucosal specimens post-radiotherapy. Preoperative high-dose radiotherapy upregulates matrilysin gene expression in rectal cancer. Matrilysin inhibition may be a useful preventive or therapeutic adjunct to radiotherapy in rectal cancer.
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PMID:Effect of preoperative radiotherapy on matrilysin gene expression in rectal cancer. 1187 42

We previously reported that vessel count, vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression are associated with metastasis formation in human colon cancer. This study was done to determine a stage of colon cancer progression where induction of these factors occurred (i.e. the angiogenic switch). We examined vessel count, VEGF, and matrix metalloproteinase (MMP)-7 expression in cancer cells and PD-ECGF expression in infiltrating cells in 25 adenomas, 35 mucosal cancers (Tis), 29 submucosal invasive cancers (T1) and 33 muscularis propria invasive cancers (T2) by immunostaining. The intensity of staining of VEGF and MMP-7 was evaluated blindly at the invasive edge and was confirmed by image analysis. Intensity of staining for these factors was graded on a scale of 0 to 3+, with 0 representing no detectable stain and 3+ representing the strongest stain. Intensites of PD-ECGF-positive infiltrating cells were similar on a scale 0 to 3+, as previous studies from our laboratory have demonstrated that PD-ECGF is expressed primarily in tumor infiltrating cells. The vessel density was 12.7+/-2.2 (SE) in adenoma, 11.8+/-1.7 in Tis, 35.0+/-6.5 in T1, and 35.2+/-5.3 in T2. There were significant differences in vessel densities between Tis and T1 (p<0.001). The intensities of VEGF expression were 0.6+/-0.1, 0.9+/-0.2, 1.7+/-0.3, and 1.8+/-0.3 for adenoma, Tis, T1 and T2, respectively, with significant differences between in Tis and T1 (p<0.001). There were also significant differences in the intensities of the expression of MMP-7 and PD-ECGF between Tis and T1. These results suggest that angiogenic switch may occur between Tis and T1, i.e. simultaneous to initiation of invasion, in the early development of colon cancer.
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PMID:The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. 1246 36

The present study describes the in vivo detection and imaging of tumour-associated MMP-7 (matrix metalloproteinase-7 or matrilysin) activity using a novel polymer-based fluorogenic substrate PB-M7VIS, which serves as a selective 'proteolytic beacon' (PB) for this metalloproteinase. PB-M7VIS is built on a PAMAM (polyamido amino) dendrimer core of 14.2 kDa, covalently coupled with an Fl (fluorescein)-labelled peptide Fl(AHX)RPLALWRS(AHX)C (where AHX stands for aminohexanoic acid) and with TMR (tetramethylrhodamine). PB-M7VIS is efficiently and selectively cleaved by MMP-7 with a k (cat)/ K (m) value of 1.9x10(5) M(-1).s(-1) as measured by the rate of increase in Fl fluorescence (up to 17-fold for the cleavage of an optimized PB-M7VIS) with minimal change in the TMR fluorescence. The K (m) value for PB-M7VIS is approx. 0.5 microM, which is approx. two orders of magnitude lower when compared with that for an analogous soluble peptide, indicating efficient interaction of MMP-7 with the synthetic polymeric substrate. With MMP-2 or -3, the k (cat)/ K (m) value for PB-M7VIS is approx. 56- or 13-fold lower respectively, when compared with MMP-7. In PB-M7VIS, Fl(AHX)RPLALWRS(AHX)C is a selective optical sensor of MMP-7 activity and TMR serves to detect both the uncleaved and cleaved reagents. Each of these can be visualized as subcutaneous fluorescent phantoms in a mouse and optically discriminated based on the ratio of green/red (Fl/TMR) fluorescence. The in vivo specificity of PB-M7VIS was tested in a mouse xenograft model. Intravenous administration of PB-M7VIS gave significantly enhanced Fl fluorescence from MMP-7-positive tumours, but not from control tumours ( P <0.0001), both originally derived from SW480 human colon cancer cells. Prior systemic treatment of the tumour-bearing mice with an MMP inhibitor BB-94 ([4-( N -hydroxyamino)-2 R -isobutyl-3 S -(thienylthiomethyl)-succinyl]-L-phenylalanine- N -methylamide), markedly decreased the Fl fluorescence over the MMP-7-positive tumour by approx. 60%. Thus PB-M7VIS functions as a PB for in vivo detection of MMP-7 activity that serves to light this optical beacon and is, therefore, a selective in vivo optical molecular imaging contrast reagent.
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PMID:Development of a novel fluorogenic proteolytic beacon for in vivo detection and imaging of tumour-associated matrix metalloproteinase-7 activity. 1455 51

MMP-7 is a member of the matrix metalloproteinase family and has been shown to be involved in early intestinal tumorigenesis. However, the factors which regulate MMP-7 gene transcription in the context of early colon cancer remain to be elucidated. Epidermal growth factor (EGF) and the EGF receptor have also been demonstrated to be important in the establishment of colon adenomas. We were therefore interested in addressing the question of whether MMP-7 could be regulated by EGF and in identifying the molecular mechanisms through which this process occurs. Herein, we have demonstrated that EGF enhanced the endogenous expression of MMP-7 in a number of human colon cancer cell lines. Analysis of the MMP-7 promoter sequence reveals the presence of a number of transcription factor binding sites including ETS and AP-1 sites. Results using PEA3, ETS and AP-1 artificial promoters showed that EGF enhanced PEA3 transcription factor activity by up to 70% in comparison to non-treated cell lines. Western blot analysis of nuclear extracts from EGF stimulated cells demonstrated that there was an increase in PEA3 protein when compared to non-treated cells. In addition, using a MAPK inhibitor we have shown that EGF can mediate this increase in PEA3 transcription factors via the MAPK pathway. Using EMSA analysis we also observed that the EGF stimulated increase in PEA3 transcription factors led to increased binding to specific ETS sites within the MMP-7 promoter. These data demonstrate for the first time that EGF directly enhances MMP-7 expression via the activation of PEA3 transcription factors.
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PMID:Epidermal growth factor upregulates matrix metalloproteinase-7 expression through activation of PEA3 transcription factors. 1513 1

The multiple intestinal neoplasia (Min/+) mouse, which carries a mutant adenomatous polyposis coli (Apc) allele, is a model for human familial colon cancer. Like the human syndrome caused by mutant APC, the Min/+ mouse syndrome shows susceptibility to tumors of other tissues, including the mammary gland. The matrix metalloproteinase (MMP) MMP-7 (matrilysin) gene is transcriptionally induced by signal transduction pathways resulting from loss of APC function, and contributes to the progression of benign and malignant intestinal epithelial cells. Mammary tumors that develop in Min/+ mice express MMP-7. To investigate whether mutant APC and MMP-7 can cooperate in mammary tumorigenesis, we compared N-ethyl-N-nitrosourea (ENU)-enhanced mammary tumor formation in Min/+ mice that were either wild-type or deficient in MMP-7. Min/+ mice lacking MMP-7 demonstrate a 60% reduction in the number of early focal lesions in the mammary gland at early, but not later, timepoints. We conclude that MMP-7 transiently influences early stage mammary tumorigenesis.
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PMID:The influence of matrix metalloproteinase-7 on early mammary tumorigenesis in the multiple intestinal neoplasia mouse. 1520 52


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