Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite its importance in cell proliferation and tumorigenesis, very little is known about the molecular mechanism underlying the regulation of phospholipase D (PLD) expression. PLD isozymes are significantly co-overexpressed with cancer marker genes in colorectal carcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment, as a mitogenic signal in colon cancer cells, selectively increases PLD1 expression in transcription and post-transcription. Moreover, experiments using intraperitoneal injection of PMA into mice showed selective PLD1 induction in the intestine and lung tissues, which suggests its physiological relevance in vivo. Therefore, we have undertaken a detailed analysis of the effects of PMA on the promoter activity of PLD genes. Protein kinase C inhibitors, but not a protein kinase A inhibitor, were found to suppress the up-regulation of PLD1 but not PLD2. Dominant-negative mutants of Ras, Raf, and MEK suppressed the induction and activity of PLD1. Moreover, depletion of the supposedly involved proteins reduced the endogenous PLD1 protein level. An important role for NFkappaB as a downstream target of ERK in PMA-induced PLD1 induction was also demonstrated using the inhibitor, small interfering RNA, chromatin immunoprecipitation assay, and site-specific mutagenesis. Furthermore, inhibitors of these signaling proteins and depletion of PLD1 suppressed PMA-induced matrix metalloproteinase-9 secretion and PLD1 induction. In conclusion, we demonstrate for the first time that induction of PLD1 through a protein kinase C/Ras/ERK/NFkappaB-dependent pathway is involved in the secretion of matrix metalloproteinase-9 in colorectal cancer cells.
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PMID:Phorbol ester up-regulates phospholipase D1 but not phospholipase D2 expression through a PKC/Ras/ERK/NFkappaB-dependent pathway and enhances matrix metalloproteinase-9 secretion in colon cancer cells. 1808 5

The matrix metalloproteinases (MMPs) can degrade various components of the extracellular matrix and are implicated in the development and progression of cancer. There is evidence suggesting an association of MMP gene polymorphisms with cancer susceptibility and/or metastasis. This paper reviews the findings on several single nucleotide polymorphisms in the collagenase, stromelysin and gelatinase genes in lung cancer, breast cancer and colorectal cancer.
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PMID:Genetic polymorphisms of matrix metalloproteinases in lung, breast and colorectal cancer. 1817 67

It has been proposed that matrix metalloproteinases (MMPs) play a role in tumor invasion. We determined protein expression of matrix metalloproteinase-9 (MMP-9) in colorectal cancer (CRC), corresponding normal mucosa and colorectal adenomas. For confirmation of immunohistochemical results MMP-9 TaqMan RT-PCR analysis was performed. Expression of MMP-9 was determined on paraffin embedded biopsy sections by immunohistochemistry in 31 CRC patients (from cancer tissue and corresponding normal mucosa) and in 30 patients with adenoma (nine adenomas with high grade of dysplasia). MMP-9 immunostaining was determined semi-quantitatively. For Taqman RT-PCR analyses normal mucosa (n = 5), adenoma without (n = 6) and with high grade dysplasia (n = 7) and CRC (n = 10) were investigated. Statistical analysis with ANOVA, LSD test and correlation analysis were performed. P value of <0.05 was considered significant. The MMP-9 expression in CRC was significantly higher compared to adenomas or the normal mucosa (P = 0.001). Significantly higher expression of MMP-9 has been observed in adenomas with high grade dysplasia compared to other adenomas or normal colon (P < 0.001). Diffuse strong MMP-9 expression was present in tumor as well as in stromal cells. In adenoma samples, dysplastic epithelial cells showed moderate intensive cytoplasmic MMP-9 expression, with a clear-cut differentiation between dysplastic and non-dysplastic areas. Staining intensity correlated with the grade of CRC. We demonstrate a significantly higher expression of MMP-9 in adenoma with high grade dysplasia-CRC sequence as compared to normal tissue. The over-expression of MMP-9 strongly suggests its association with colorectal carcinogenesis.
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PMID:Matrix metalloproteinase-9 expression in the normal mucosa-adenoma-dysplasia-adenocarcinoma sequence of the colon. 1834 34

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and membrane-type matrix metalloproteinase 1 (MT1-MMP) are involved in colorectal cancer invasion and metastasis. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) inhibits MMP-2, MMP-9 and MT1-MMP. We examined the clinicopathological significance of the relative expression of these genes in patients with colorectal cancer, especially with regard to metastasis. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal carcinoma. MMP-2, MMP-9, MT1-MMP, RECK and beta-actin mRNA of cancer tissue and adjacent normal mucosa were measured by quantitative real-time reverse-transcriptase polymerase chain reaction. MT1-MMP gene expression was higher in cancer tissue than in adjacent normal mucosa. In contrast, MMP-2, MMP-9 and RECK gene expression levels were lower in cancer tissue than in adjacent normal mucosa. As for the relationship between the gene expression and clinicopathological factors, MMP-2 expression correlated with the depth of invasion, venous invasion and liver metastasis; MMP-9 and RECK expression correlated with venous invasion. There were positive correlations among the gene expression levels of MMP-2, MMP-9 and RECK. MMP-2 gene expression was considered a useful predictor of liver metastasis from colorectal cancer.
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PMID:Clinicopathological significance of the gene expression of matrix metalloproteinases and reversion-inducing cysteine-rich protein with Kazal motifs in patients with colorectal cancer: MMP-2 gene expression is a useful predictor of liver metastasis from colorectal cancer. 1842 89

The aim of this study is to investigate the expression of AP-4, VEGF, and MMP-9 genes in human colorectal cancer. The expression pattern of activator protein-4 in 160 colorectal cancer compared with 32 colorectal adenomas and 32 normal colorectal tissues is demonstrated by tissue microarray-immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction. Apoptosis status using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling by comparing activator protein-4 positive versus activator protein-4 negative colorectal cancer is also assessed. The messenger RNA levels of vascular endothelial growth factor and matrix metalloproteinase-9 expression in activator protein-4 positive and negative colorectal cancer were measured using real-time reverse transcriptase- polymerase chain reaction. The activator protein-4 expression in normal colorectal tissue, adenoma, and adenocarcinoma were 4 of 32, 8 of 32, and 78 of 160, respectively. It is shown that the activator protein-4 expression was significantly correlated with the progression of colorectal cancer (P < .01) and differentiation and lymph node metastasis (P < .01). Our results also presented that the activator protein-4 expression was associated with the expression of matrix metalloproteinase-9 and vascular endothelial growth factor in the advanced colorectal cancer.
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PMID:Upregulation of activator protein-4 in human colorectal cancer with metastasis. 1848 Mar 85

The expression and activation of matrix metalloproteinases (MMPs) by tumor cells is correlated with invasive and metastatic potential. The purpose of this study was to examine the impact of increased membrane type 1 matrix metalloproteinase (MT1-MMP) expression on liver metastatic potential utilizing human colorectal cancer (CRC) cell lines. Three human CRC cell lines, DLD1, HCT116 and HT29, were stably transfected with the MT1-MMP cDNA, and experimental liver metastasis was established by injecting the cells into the spleens of nude mice. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed increased expression of MT1-MMP mRNA in the stable tranfectants. In vitro analysis by gelatin zymography and morphological survey demonstrated that MT1-MMP transfectants displayed a matured gelatinolytic activity and invasive properties when cultured in 3D collagen gel, indicating that transduced MT1-MMP cDNA was functional. Although there was no difference in cell proliferation rate between MT1-MMP overexpressing cells and the Mock control cells, in vivo experiments indicated that the liver metastatic ability was not affected by MT1-MMP overexpression. Our findings indicated that conditional MT1-MMP overexpression was insufficient to increase experimental liver metastasis, suggesting a more complicated mechanism may be involved in the activation and regulation of MMPs cascades in vivo.
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PMID:Overexpression of MT1-MMP is insufficient to increase experimental liver metastasis of human colon cancer cells. 1902 Jul 73

Colorectal carcinoma (CRC) is often lethal when invasion and/or metastasis occur. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme involved in prostaglandin (including PGE(2)) bio-inactivation, is down-expressed in several epithelial malignancies including CRC. Although its role in the suppression of colon tumorigenesis has been well learned, little is known about the role of 15-PGDH in the process of tumor metastasis. Here, we tested the hypothesis that 15-PGDH over-expression in CRC cells results in decreased cell motility and invasion. In this study, 15-PGDH was re-expressed in SW480 cells by the use of gene transient transfection with eukaryotic expression vector pcDNA3.1-PGDH. We confirmed the over-expression of 15-PGDH protein by Western blot and enzymatic activity assay. The cell motility was tested by counting the number of cells crossing an 8-micron pore size PET membrane and by measuring cells migration distance through wound healing assay. Furthermore, cell invasive activity was evaluated by counting the number of cells invading through a Matrigel-coated membrane simulating basement membrane. The effects of 15-PGDH on the adhesion were investigated by MTT assay. Ectopic expression of 15-PGDH in SW480 cancer cells significantly inhibited the cell migratory and invasive capacity in vitro by approximately 1.9- and 8.4-fold, respectively. To test the hypothesis that 15-PGDH affects proteases and inactivates extracellular matrix (ECM), Western blot and gelatin zymography were performed by using serum-free conditioned medium. The results showed that re-expression of 15-PGDH suppresed matrix metalloproteinase-2 (MMP2) synthesis and secretion. In addition, the analysis of the MMP2 activity indicated that re-expression of 15-PGDH could inhibit activation of MMP2. Furthermore, we found that 15-PGDH inhibited cell adhesion to ECM and reduced CD44 expression in SW480 cell. Taken together, these results suggest that induced 15-PGDH expression may contribute to the inhibition of the invasive and metastatic capacity of colon cancer cells in vitro.
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PMID:Suppression of invasive properties of colorectal carcinoma SW480 cells by 15-hydroxyprostaglandin dehydrogenase gene. 1903 72

We present a case of multiple colorectal liver metastases with macroscopic portal vein thrombi. A 55-year-old woman presented to us with rectosigmoid cancer and presented with two liver metastases. The tumor in the posterior sector was associated with invasion of first order branches of the portal vein. We performed low anterior resection, hepatic posterior sectorectomy and partial left anterior sectorectomy. Both the colorectal cancer and liver tumors exhibited histological characteristics of moderately differentiated adenocarcinoma with a substantial amount of mucin production. The liver metastases were associated with prominent tumor thrombi in many branches of the portal vein. Stronger staining for endoglin (CD 105) than for Fas ligand (Fas L) and matrix metalloproteinase (MMP-2) was observed in both the colorectal cancer and metastatic liver tumor cells. Expression of the vascular endothelial growth factor within the tumor cells was seen in both the colorectal cancer as well as the metastatic liver tumor cells. Six months after the operation, she was diagnosed to have multiple, more than about 20 liver metastases, and in 9 months after the operation, the patient died. The colorectal cancer with liver metastases associated with portal vein tumor thrombosis was poor prognosis, found neoplastic microvessel formation.
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PMID:Macroscopic portal vein tumor thrombi of liver metastasis from colorectal cancer. 1908 48

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3-5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73-92) ng/ml, 2372 (95% CI, 2121-2623) ng/ml, and 10.6 (95% CI, 7.21-13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675-2292) and a significant increase in MMP-7 levels to 14.6 (7.6-21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.
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PMID:Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer. 1910 98

Elevated deoxycholic acid (DCA), mutations in the adenomatous polyposis coli (APC) gene and chronic inflammation are associated with increased risk of colorectal cancer. APC status was manipulated to determine whether DCA mediates inflammatory molecules in normal or initiated colonic mucosa. DCA increased steady state mRNA and protein levels of CXCL8 in cells which do not express wild-type APC. Steady-state CXCL8 mRNA and protein were suppressed when cells with conditional expression of wild-type APC were exposed to DCA. Immunostaining did not detect CXCL8 in normal human colonic mucosa. CXCL8 was expressed in adenomatous polyps and adenocarcinomas. CXCL8 expression correlated with nuclear beta-catenin localization in epithelial cells of adenomas, but was associated with endothelial cells and neutrophils in the adenocarcinomas. DCA-mediated CXCL8 promoter-reporter activity was elevated in a mutant APC background. Wild-type APC suppressed this effect. Mutation of activator protein-1 (AP-1) or nuclear factor kappa B (NF-kappaB) sites suppressed the activation of the CXCL8 promoter-reporter by DCA. Chromatin immunoprecipitation revealed that AP-1 and NF-kappaB binding to the 5'-promoter of CXCL8 was induced by DCA. The beta-catenin transcription factor was bound to the 5'-promoter of CXCL8 in the absence or presence of DCA. Phenotypic assays determined that DCA-mediated invasion was blocked by antibody-directed against CXCL8 or wild-type APC. CXCL8 exposure led to matrix metalloproteinase-2 production and increased invasion on laminin-coated filters. These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors.
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PMID:Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer. 1917 96


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