Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulating evidences that carcinogenesis requires multiple gene alterations of oncogenes and tumor suppressor genes have recently emerged. In addition, genes related to invasion and metastasis are also important in understanding development of colorectal cancer. In this study, clinical significance and application of tumor suppressor genes and invasion related genes such as APC (adenomatous polyposis coli), DCC (deleted in colorectal carcinoma) tumor suppressor genes and invasion related gene, matrilysin were studied. In the mouse tumor induced by mutagen contained in cooked food, PhIP (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine), nonsense mutations of APC gene that is similar to human colorectal cancer have been observed. These results suggested the quite interesting issue of mutagen contained in daily food having etiological role of colorectal cancer. DCC gene alteration, decreased expression of DCC mRNA was detected in 60% of advanced colorectal cancer. In all cases with liver metastasis, DCC expression was absent or markedly decreased, a finding that detection of DCC expression have an clinical importance that predicts metastatic potential of colorectal cancer. Matrilysin, the member of MMPs (matrix metalloproteinases) which degrade matrix components such as type IV collagen, laminin or fibronectin. In most of colorectal cancer, matrilysin was overexpressed in tumor cells. Matrilysin-transfected colorectal cancer cells showed more invasive ability in vitro and gained metastatic potential in SCID mice. Suppression of matrilysin expression by treated with all-trans retinoic acid (ATRA) or introduction of anti-sense matrilysin decreased the invasive ability in vitro. This result suggests that matrilysin plays an important role in invasion and metastasis and have a possibility of new anti-invasion therapy.
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PMID:[Genetic diagnosis of colorectal cancer]. 872 69

Both the matrix metalloproteinase matrilysin and the prostaglandin H synthase cyclooxygenase-2 (Cox-2), are thought to play key roles in colorectal carcinogenesis. These enzymes are overexpressed in 85-90% of human colorectal cancers. Furthermore, mice carrying an adenomatous polyposis coli germline mutation that are also nullizygous for either matrilysin or Cox-2 display a significant reduction in tumor multiplicity. To determine if there is a direct link between matrilysin and Cox-2, their expression was characterized in two mouse models of intestinal carcinogenesis and in human colorectal tumor samples. Both matrilysin and Cox-2 expression was increased in the mouse models and in the human colorectal cancers; however, immunohistochemistry and in situ hybridization indicated that their localization within the tumors was different. In the mouse models, Cox-2 was expressed in the superficial stroma, whereas matrilysin expression was localized exclusively to the neoplastic epithelium. In contrast, in human colorectal cancers, both Cox-2 and matrilysin were expressed in the neoplastic epithelium. Although over 80% of the specimens expressed both matrilysin and Cox-2, the levels and localization of matrilysin and Cox-2 expression were distinct. Cox-2 expression was strongest in well-differentiated areas, and matrilysin immunostaining was strongest in the more dysplastic and invasive regions of the tumor. These results indicate that these two important modulators of colorectal tumorigenesis are differentially expressed and imply that the therapeutic benefit may be improved by combination therapy utilizing selective Cox-2 and matrilysin inhibitors.
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PMID:Differential expression of matrilysin and cyclooxygenase-2 in intestinal and colorectal neoplasms. 1020 2

The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. beta-Catenin-Tcf (BCT)-dependent Wnt signaling is influenced by the short-chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT-dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT-116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild-type HCT-116 cells having mutant beta-catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT-dependent expression of the Tcf-TK, matrilysin and cyclin D1 promoters, whereas in HCT-116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex-DNA binding. Butyrate reduces the expression of Tcf4 in HCT-116 cells, consistent with the induction by butyrate of Tcf-repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT-116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate.
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PMID:Cell type- and promoter-dependent modulation of the Wnt signaling pathway by sodium butyrate. 1177 42

In colorectal carcinomas, loss-of-function mutations of the adenomatous polyposis coli (APC) tumor suppressor gene lead to a nuclear accumulation of the oncogenic transcriptional activator beta-catenin, predominantly at the invasive front within the tumor host interface. Various identified genes activated by beta-catenin are associated with tumor invasion. One prerequisite for malignant tumor invasion is the ability of tumor cells to migrate. We recently described the gamma2 chain of laminin as another beta-catenin target gene. Fragments of the laminin gamma2 chain, resulting from cleavage by the membrane type 1 matrix metalloproteinase (MT1-MMP), are strong inducers of epithelial cell migration. We here show a coordinated expression of nuclear beta-catenin, its target gene and MT1-MMP substrate laminin gamma2 chain, as well as MT1-MMP in tumor cells at invasive regions of colorectal carcinomas. We further demonstrate that MT1-MMP expression is regulated by beta-catenin/TCF through a TCF binding site in its promoter. These results suggest that nuclear beta-catenin activates the coordinated expression of the interacting proinvasive proteins laminin gamma2 chain and MT1-MMP, thereby leading to a promigratory activity at the invasive front of colorectal cancers. This further supports an important role of beta-catenin for invasion and metastasis of colorectal carcinomas.
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PMID:Beta-catenin activates a coordinated expression of the proinvasive factors laminin-5 gamma2 chain and MT1-MMP in colorectal carcinomas. 1463 22

Heterozygous mutations in adenomatous polyposis coli (APC) is an early event in inheritable and sporadic colon cancer development. We recently found reduced connexin (Cx43) expression in intestinal cell lines with heterozygous Apc mutation. In this study we investigated Cx expression and the role of one mutated Apc allele in epithelia of multiple intestinal neoplasia (Min) mouse intestines by immunohistochemistry. Cx43 was not expressed in intestinal epithelia of Min and wild-type mice. Cx32 was specifically expressed in enterochromaffin cells in both mice types, and in Paneth cells of wild-type mice. In contrast, Min mice had nearly undetectable level of Cx32 in Paneth cells. Isolated small intestinal crypts from Min mice had markedly increased secretion of both lysozyme and matrilysin compared with wild-type mice. Absence of matrilysin in Min mice reduces adenoma development. Reduced Cx32 and increased matrilysin secretion from Paneth cells could be important to neoplastic development in the intestine.
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PMID:Truncated mouse adenomatous polyposis coli reduces connexin32 content and increases matrilysin secretion from Paneth cells. 1519 46

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