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Claudin-3 and Claudin-4 Expression in Ovarian Epithelial Cells Enhances Invasion and Is Associated with Increased Matrix Metalloproteinase-2 Activity

Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland

Requests for reprints: Patrice J. Morin, Laboratory of Cellular and Molecular Biology, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224. Phone: 410-558-8506; Fax: 410-558-8386; E-mail: morinp{at}grc.nia.nih.gov.

Claudin proteins form a large family of integral membrane proteins crucial for tight junction formation and function. Our previous studies have revealed that claudin-3 and claudin-4 proteins are highly overexpressed in ovarian cancer. To clarify the roles of claudins in ovarian tumorigenesis, we have generated human ovarian surface epithelial (HOSE) cells constitutively expressing wild-type claudin-3 and claudin-4. Expression of these claudins in HOSE cells increased cell invasion and motility as measured by Boyden chamber assays and wound-healing experiments. Conversely, small interfering RNA (siRNA)–mediated knockdown of claudin-3 and claudin-4 expression in ovarian cancer cell lines reduced invasion. Claudin expression also increased cell survival in HOSE cells but did not significantly affect cell proliferation. Moreover, the claudin-expressing ovarian epithelial cells were found to have increased matrix metalloproteinase-2 (MMP-2) activity indicating that claudin-mediated increased invasion might be mediated through the activation of MMP proteins. However, siRNA inactivation of claudins in ovarian cancer cell lines did not have a significant effect on the high endogenous MMP-2 activity present in these cells, showing that malignant cells have alternative or additional pathways to fully activate MMP-2. Taken together, our results suggest that claudin overexpression may promote ovarian tumorigenesis and metastasis through increased invasion and survival of tumor cells.

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