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E-Cadherin Regulates Human Nanos1, which Interacts with p120ctn and Induces Tumor Cell Migration and Invasion

¹ Department for Molecular Biomedical Research, VIB and Ghent University, Ghent, Belgium; ² Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium; ³ The Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁴ Institut National de la Santé et de la Recherche Medicale U514, Institut Fédératif de Recherche 53, and Laboratoire Pol Bouin, Centre Hospitalier Universitaire Maison Blanche, Reims, France

Requests for reprints: Frans van Roy, Department for Molecular Biomedical Research, VIB-Ghent University, Technologiepark 927, B-9052 Ghent-Zwijnaarde, Belgium. Phone: 32-9-331-3604; Fax: 32-9-331-3500; E-mail: f.vanroy{at}dmbr.ugent.be.

Down-regulation of the epithelial cell-cell adhesion molecule E-cadherin is frequently associated with tumor formation and progression. Besides its role in physical cell-cell adhesion, E-cadherin is also thought to be involved in intracellular signaling in normal epithelial cells. In these cells, the Armadillo catenin p120ctn binds to the cytoplasmic domain of E-cadherin and stabilizes the adhesion complexes. On loss of E-cadherin, cytoplasmic p120ctn might accumulate and contribute to tumor malignancy. We used suppression subtractive hybridization to search for genes regulated by E-cadherin expression. We isolated human Nanos1 as a transcript of which levels decrease on E-cadherin reexpression in a human breast cancer cell line. The hNanos1 protein bears a COOH-terminal (CCHC)₂ zinc finger domain and belongs to an evolutionarily conserved protein family sharing functions in germ cell development in both vertebrates and invertebrates. We found an inverse correlation between E-cadherin and hNanos1 expression in various cell lines and under diverse conditions. Conditional expression of hNanos1 in human colorectal DLD1 cancer cells functionally abolished cell-cell adhesion. It induced cytoplasmic translocation of p120ctn, as well as strong migratory and invasive properties. We also found that the NH₂-terminal domain of hNanos1, which is conserved only among mammals, interacts with p120ctn. hNanos1 counteracted the stimulatory effect of p120ctn on cell protrusion formation. Together, these findings describe a new function for hNanos1 as a downstream effector of E-cadherin loss contributing to tumor progression. Targeting hNanos1 might be a promising strategy in the treatment of E-cadherin–negative tumors in particular. (Cancer Res 2006; 12(20): 10007-15)

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