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Membrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells.

Abstract : The acquisition of a migratory/invasive phenotype by tumor cells is characterized by the loss of cell-cell adhesion contacts and the expression of degradative properties. In this study, we examined the effect of the disorganization of occludin/zonula occludens (ZO)-1 tight junction (TJ) complexes on the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP). We first compared the expression of MT1-MMP and the localization of occludin/ZO-1 complexes in breast tumor cell lines displaying various degrees of invasiveness. We showed that the expression of MT1-MMP in invasive breast tumor cell lines correlates with the absence of occludin and with a cytoplasmic localization of ZO-1. In contrast, noninvasive cell lines displayed a membrane staining for both ZO-1 and occludin and did not express MT1-MMP. In vivo, cytoplasmic ZO-1 and MT1-MMP could be detected in invasive tumor clusters of human breast carcinomas. We then used RNA interference strategy to inhibit ZO-1 expression in invasive BT549 cells and to evaluate the effect of ZO-1 down-regulation on MT1-MMP expression. We observed that ZO-1 small interfering RNA transfection down-regulates MT1-MMP mRNAs and proteins and subsequently decreases the ability of tumor cells to invade a reconstituted basement membrane in a Boyden chamber assay. Inversely, transfection of expression vectors encoding wild-type ZO-1 or the NH2-terminal fragment of ZO-1 comprising the PSD95/DLG/ZO-1 domains in BT549 activated a human MT1-MMP promoter luciferase reporter construct and increased cell invasiveness. Such transfections concomitantly activated the beta-catenin/TCF/LEF pathway. Our results therefore show that ZO-1, besides its structural role in TJ assembly, can intervene in signaling events promoting tumor cell invasion.
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https://www.hal.inserm.fr/inserm-00145401
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Submitted on : Wednesday, September 22, 2010 - 2:09:48 PM
Last modification on : Tuesday, January 14, 2020 - 3:24:07 PM
Long-term archiving on: : Thursday, December 23, 2010 - 2:26:46 AM

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Myriam Polette, Christine Gilles, Béatrice Nawrocki-Raby, Jouko Lohi, Walter Hunziker, et al.. Membrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells.. Cancer Research, American Association for Cancer Research, 2005, 65 (17), pp.7691-8. ⟨10.1158/0008-5472.CAN-04-4230⟩. ⟨inserm-00145401⟩

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