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

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 17; pp. 7691 - 7698
• Main Authors: POLETTE, Myriam, GILLES, Christine, NAWROCKI-RABY, Béatrice, LOHI, Jouko, HUNZIKER, Walter, FOIDART, Jean-Michel, BIREMBAUT, Philippe
• Format: Journal Article Web Resource
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2005; American Association for Cancer Research, Inc. (AACR)
• Subjects: beta Catenin; Biological and medical sciences; Breast Neoplasms; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Cytoplasm; Cytoplasm - metabolism; Cytoskeletal Proteins; Cytoskeletal Proteins - genetics; DNA, Complementary; DNA, Complementary - genetics; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Human health and pathology; Human health sciences; Humans; Life Sciences; Mammary gland diseases; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Membrane Proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metalloend; Metalloendopeptidases - biosynthesis; Metalloendopeptidases - genetics; Neoplasm Invasiveness; Oncologie; Oncology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; Pulmonology and respiratory tract; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sciences de la santé humaine; Trans-Activators - genetics; Transcriptional Activation; Transfection; Tumors; Zonula Occludens-1 Protein; Human; Enzyme; Cell junction; Metalloendopeptidases; Breast cancer; Malignant tumor; Gene expression; Occludin; Mammary gland diseases; Peptidases; Regulation(control); Hydrolases; Tight junction; Tumor cell; Interstitial collagenase
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-4230

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.