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Defective Claudin-7 Regulation by Tcf-4 and Sox-9 Disrupts the Polarity and Increases the Tumorigenicity of Colorectal Cancer Cells

¹ Centre National de la Recherche Scientifique, UMR 5203, Institut de Génomique Fonctionnelle, and INSERM U661, and Université Montpellier 1, 2, Montpellier, France; ² Institut de Recherche en Cancérologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France; ³ Department of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia; and ⁴ Service d'Hépato-Gastroentérologie, CHU Carémeau, Nîmes, France

Requests for reprints: Frédéric Hollande, Cellular and Molecular Oncology Department, 141 rue de la Cardonille, 34094 Montpellier cedex, France. Phone: 33-46766-8144; Fax: 33-46766-8149; E-mail: fhollande{at}univ-montp1.fr.

Key Words: claudin-7 • colorectal carcinoma • Tcf-4 • Sox-9 • polarization

Tight junctions have recently emerged as essential signaling regulators of proliferation and differentiation in epithelial tissues. Here, we aimed to identify the factors regulating claudin-7 expression in the colon, and analyzed the consequences of claudin-7 overexpression in colorectal carcinoma (CRC). In healthy human colonic crypts, claudin-7 expression was found to be low in the stem/progenitor cell compartment, where Tcf-4 activity is high, but strong in differentiated and postmitotic cells, where Tcf-4 is inactive. In contrast, claudin-7 was overexpressed in areas with high Tcf-4 target gene levels in CRC samples. In vitro, Tcf-4 was able to repress claudin-7 expression, and the high mobility group–box transcription factor Sox-9 was identified as an essential mediator of this effect. Claudin-7 was strongly expressed in the intestine of Sox-9–deficient mice and in CRC cells with low Sox transcriptional activity. Sox-9 overexpression in these cells reinstated claudin-7 repression, and residual claudin-7 was no longer localized along the basolateral membrane, but was instead restricted to tight junctions. Using HT-29Cl.16E CRC cell spheroids, we found that Sox-9–induced polarization was completely reversed after virus-mediated claudin-7 overexpression. Claudin-7 overexpression in this context increased Tcf-4 target gene expression, proliferation, and tumorigenicity after injection in nude mice. Our results indicate that Tcf-4 maintains low levels of claudin-7 at the bottom of colonic crypts, acting via Sox-9. This negative regulation seems to be defective in CRC, possibly due to decreased Sox-9 activity, and the resulting claudin-7 overexpression promotes a loss of tumor cell polarization and contributes to tumorigenesis. [Cancer Res 2008;68(11):4258–68]