E-Cadherin mediates MMP down-regulation in highly invasive bronchial tumor cells.
ABSTRACT The disorganization of E-cadherin/catenin complexes and the overexpression of matrix metalloproteinases (MMPs) are frequently involved in the capacity of epithelial cells to acquire an invasive phenotype. The functional link between E-cadherin and MMPs was studied by transfecting invasive bronchial BZR tumor cells with human E-cadherin cDNA. Using different in vitro (cell dispersion, modified Boyden chamber) and in vivo assays (human airway epithelial xenograft), we showed that E-cadherin-positive clones displayed a decrease of invasive abilities. As shown by immunoprecipitation, the re-expressed E-cadherin was able to sequestrate one part of free cytoplasmic beta-catenin in BZR cells. The decrease of beta-catenin transcriptional activity in E-cadherin-transfected clones was demonstrated using the TOP-FLASH reporter construct. Finally, we observed a decrease of MMP-1, MMP-3, MMP-9, and MT1-MMP, both at the mRNA and at the protein levels, in E-cadherin-positive clones whereas no changes in MMP-2, TIMP-1, or TIMP-2 were observed when compared with control clones. Moreover, zymography analysis revealed a loss of MMP-2 activation ability in E-cadherin-positive clones treated with the concanavalin A lectin. These data demonstrate a direct role of E-cadherin/catenin complex organization in the regulation of MMPs and suggest an implication of this regulation in the expression of an invasive phenotype by bronchial tumor cells.
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ABSTRACT: To maintain homeostasis of bone, the production of osteoblasts and osteoclasts is tightly regulated. At the local level, hormones and cytokines control formation of osteoclasts from hemopoietic precursors by acting upon osteoblastic-stromal cells and in some cases also upon cells of the immune system. Osteoblasts regulate osteoclast formation by providing physical support and cytokines such as M-CSF and IL-11, which promote osteoclast differentiation. Osteoblasts are also a source of IL-18, which limits osteoclast formation. The requirement of contact between osteoblasts and hemopoietic cells for successful osteoclast formation led to a concept of a membrane-anchored stromal cell molecule that programs osteoclast differentiation. This mechanism has been highlighted by the discovery of osteoprotegerin (OPG), a soluble tumor necrosis factor (TNF) family member that inhibits osteoclast formation. The ligand for OPG is a novel transmembrane TNF receptor superfamily member, the osteoclast differentiating factor (ODF). The recognition of the osteoprotegerin/osteoprotegerin-ligand axis will lead to new insights into the control of osteoclast differentiation by interleukins.Critical Reviews in Eukaryotic Gene Expression 02/1998; 8(2):107-23. · 3.08 Impact Factor