Proliferative effects of apical, but not basal, matrix metalloproteinase-7 activity in polarized MDCK cells.
Matrix metalloproteinase-7 (MMP-7) is primarily expressed in glandular epithelium. Therefore, its mechanism of action may be influenced by its regulated vectorial release to either the apical and/or basolateral compartments, where it would act on its various substrates. To gain a better understanding of where MMP-7 is released in polarized epithelium, we have analyzed its pattern of secretion in polarized MDCK cells expressing stably transfected human MMP-7 (MDCK-MMP-7), and HCA-7 and Caco2 human colon cancer cell lines. In all cell lines, latent MMP-7 was secreted to both cellular compartments, but was 1.5- to 3-fold more abundant in the basolateral compartment as compared to the apical. However, studies in the MDCK system demonstrated that MMP-7 activity was 2-fold greater in the apical compartment of MDCK-MMP-7(HIGH)-polarized monolayers, which suggests the apical co-release of an MMP-7 activator. In functional assays, MMP-7 over-expression increased cell saturation density as a result of increased cell proliferation with no effect on apoptosis. Apical MMP-7 activity was shown to be responsible for the proliferative effect, which occurred, as demonstrated by media transfer experiments, through cleavage of an apical substrate and not through the generation of a soluble factor. Taken together, our findings demonstrate the importance of MMP-7 secretion in relation to its mechanism of action when expressed in a polarized epithelium.
Harrell
Permila C
PC
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
McCawley
Lisa J
LJ
Fingleton
Barbara
B
McIntyre
J Oliver
JO
Matrisian
Lynn M
LM
D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D016764:Cell Polarity; D049109:Cell Proliferation; D004285:Dogs; D006801:Humans; D020783:Matrix Metalloproteinase 7; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D008666:Metalloendopeptidases; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7