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ABSTRACT: Members of the matrix metalloproteinase (MMP) family of enzymes play a critical role in extracellular matrix remodeling in a number of normal and pathologic processes. Accordingly, activation of MMP gene expression is tightly regulated at the level of transcription by specific transcription factors, most notably following exposure to inflammatory cytokines. Recent studies with 5-aza-2'-deoxycytidine (5-aza-dC), a specific DNA methylase inhibitor, also suggest that epigenetic processes contribute to the regulation of MMP expression. Although inflammation-related aberrant patterns of DNA methylation have been described, a mechanistic link between inflammation and epigenetic alterations in the control of MMP expression remains unclear. Here, we provide evidence that increased MMP-3 expression by 5-aza-dC is modulated by interleukin-1 (IL-1). More specifically, we found that stimulation with IL-1, but not with IL-6 or TNFα, significantly increased the hypomethylation status of the MMP-3 promoter to a level similar to that found in dnmt1/dnmt3b-deficient HCT116 (DKO) cells. Furthermore, we showed that increased MMP-3 expression by 5-aza-dC was associated with increased expression and activity of specific transcription factors known to regulate MMP-3 expression. In fact, treatment with 5-aza-dC was obligatory for some transcription factors to trigger an increase in MMP-3 expression, such as Ap-1. In contrast, CCAAT enhancer-binding proteins and E-twenty six were capable of inducing MMP-3 alone. Overall, these findings provide a novel perspective of the collaborative role of 5-aza-dC and inflammatory cytokines with specific transcription factors that are normally involved in MMP-3 expression.
International Journal of Cancer 12/2010; 129(9):2083-92. · 5.44 Impact Factor
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ABSTRACT: Recent studies have reported that elevated levels of galectin-7 in different types of cancer. The mechanisms underlying its abnormal regulation in cancer cells remain, however, unknown. Here, we have examined the relationship between galectin-7 and p53, a gene previously associated with upregulation of galectin-7. While RNA and protein analyses revealed a consistent and irreversible upregulation of galectin-7 throughout progression of lymphoma, no correlation with p53 was found. In fact, most of the lymphoma cell lines expressing high levels of galectin-7 did not express any detectable level of p53, although expressed p21(Waf1/Cip1) gene following doxorubicin treatment, indicating that p53 was functional in these cells. Methylation-specific polymerase chain reaction (MS-PCR) analyses rather suggested that galectin-7 expression was associated with changes in DNA methylation. This conclusion was supported by data using demethylating agent 5-aza-dC. Furthermore, disruption of the DNA methylases dnmt1 and dnmt3a induced galectin-7. Collectively, our data suggest that abnormal expression of galectin-7 in lymphoma cells is not dependent on p53, but is rather associated with DNA hypomethylation.
Biochemical and Biophysical Research Communications 08/2009; 387(3):425-9. · 2.48 Impact Factor
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ABSTRACT: Background: Galectins are a family of proteins defined by having at least one characteristic carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. Over the recent years, with a better understanding of their role in normal and pathological conditions, they have emerged as promising diagnostic and therapeutic targets in cancer. Whereas most of these studies have focused on galectin-1 and galectin-3, very little attention has been paid to galectin-7, a member of the family that has recently been associated with various forms of cancer. Objective: We review the role of galectin-7 in cancer and examine the possible directions that could be exploited to inhibit its role in cancer on the basis of recently identified galectin ligands. Conclusion: Although efforts have been made to develop drugs aimed at inhibiting the cancer-promoting propensity of galectins, most of these inhibitors were specific for the CRD region of the molecule and have focused on extracellular functions of galectins. However, galectins may also be involved in protein-protein interactions, most notably in the nucleus. As galectin-7 is expressed in the cytoplasm and the nucleus in cancer cells, it will be important to investigate its nucleocytoplasmic trafficking and how putative drugs will affect its functions in cancer.
Expert Opinion on Drug Discovery 06/2009; 4(6):611-620. · 2.12 Impact Factor
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ABSTRACT: Genome-wide DNA hypomethylation is a critical mechanism underlying neoplastic transformation. Thus, genes that are suppressed in normal tissues or in specific cell types may become aberrantly expressed in neoplasia. To determine whether DNA methylation can modulate matrix metalloproteinase (mmp) gene expression, we have used a genetically engineered cell line in which both key DNA methyltransferase genes, Dnmt-1 and Dnmt-3b, were removed by homologous recombination. We found that cells bearing a dual knock-out of both Dnmt-1 and Dnmt-3b genes induced de novo expression of mmp-3 gene, but not that of mmp-1 and mmp-2. Furthermore, treatment of the wild-type cells with DNA methylase inhibitors 5-aza-dC and zebularine also induced mmp-3 gene expression. On the other hand, in vitro methylation of the mmp-3 promoter suppressed its transcriptional activity. Finally, we found that induction of mmp-3 and mmp-10 gene expression by hypomethylation was cell-specific, suggesting that epigenetic changes may predispose cells to express stromelysin genes.
Biochemical and Biophysical Research Communications 05/2006; 342(4):1233-9. · 2.48 Impact Factor
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ABSTRACT: To form tumors successfully at sites remote from the primary tumor, metastatic cells must be endowed with particular properties. They must detach from the primary tumor and enter the blood circulation, where they must resist hemodynamic shearstress, "home" to the target organ, successfully extravasate, and then migrate through dense stroma to a site favorable for tumor growth. Recent results with genetically engineered mouse models have generated data which clearly challenge the classic dogma stating that matrix metalloproteinases (MMPs) promote metastasis solely by modulating the remodeling of extracellular matrix (ECM). Instead, it is becoming clear that MMPs and their natural inhibitors have multiple biological functions that not only challenge our view on how MMPs promote metastasis, but also raise for the first time the idea that secretion of MMPs by the host could protect it from tumor growth, at least in some types of cancer or at specific stages of tumor progression.
Critical Reviews in Immunology 02/2005; 25(6):493-523. · 3.32 Impact Factor
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ABSTRACT: The need to pharmacologically control the proteolytic activity of matrix metalloproteinases (MMPs) has been commonly acknowledged, despite its limited efficacy in clinical trials. Among the reasons that explain this failure is our limited understanding of the signals that control the expression of MMPs in different cell types during different pathological conditions. Thus, future therapies must rely on more selective approaches. With the continually increasing body of proof implicating MMPs in a large number of diseases, it has become a priority to establish the pertinence of molecules involved in the signalling pathways leading to the expression of these enzymes. MMP-9 is a case in point: its dramatic overexpression in cancer and various inflammatory conditions clearly points to the molecular mechanisms controlling its expression as a potential target for eventual rational therapeutic intervention. In this article, recent progress in the signalling pathways that regulate MMP-9 expression is reviewed, and the latest strategies to be considered in the search for a specific inhibitor of its expression are presented.
Expert opinion on therapeutic targets 11/2004; 8(5):473-89. · 3.72 Impact Factor
