Abstract
Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG). Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1) loss of cell-cell contact, (2) increased cell migration, (3) a loss of epithelial cell polarization and (4) increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.
Highlights
The matrix metalloproteinase (MMP) family of zinc-dependent enzymes comprises 23 members in man [1]
Using confluent Madin Darby Canine Kidney (MDCK) cells, we observed by immunofluorescence that the addition of exogenous MMP-7 resulted in a loss of cell-cell contact as assessed by immunofluorescent localization of β-catenin (Figure 1(a))
We observed that the endogenous expression of MMP-7 in the C57MG cell line did not impact the expression of other MMPs such as MMP-2 and MMP-9
Summary
The matrix metalloproteinase (MMP) family of zinc-dependent enzymes comprises 23 members in man [1]. MMPs are typically thought of as degradative enzymes with the ability to cleave extracellular matrix proteins such as collagen and fibronectin, recent literature suggests that their dominant role is as signal-altering molecules [2]. MMP-7, in particular, has several in vivoverified substrates, none of which are typical extracellular matrix proteins [3]. These nonmatrix-degrading functions of MMPs vastly expand the ways in which they can contribute to various pathologies, including tumor progression. In previous studies we have identified several growth and death factors as substrates for MMP-7 that affect tumor behavior [4,5,6,7]. We identified the adhesion molecule Ecadherin as an MMP-7 substrate and showed that one of the products of E-cadherin cleavage, the 80 kDa ectodomain, could promote invasive activity in a paracrine fashion [8]
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