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R-Cadherin Expression Inhibits Myogenesis and Induces Myoblast Transformation via Rac1 GTPase

¹ CRBM, Université Montpellier 2 et 1, Centre National de la Recherche Scientifique UMR and ² Institut de Recherche en Cancérologie de Montpellier, Institut National de la Sante et de la Recherche Medicale, Université Montpellier 1, CRLC Val d'Aurelle Paul Lamarque, Montpellier, France

Requests for reprints: Cecile Gauthier-Rouvière, CRBM, Centre National de la Recherche Scientifique, UMR 5237, 1919 Route de Mende, 34293 Montpellier Cedex, France. Phone: 33467613355; Fax: 33467521559; E-mail: cecile.gauthier{at}crbm.cnrs.fr.

Key Words: Cadherins • Rac1 GTPase • Rhabdomyosarcoma • Transformation • Myogenesis

Cadherins are transmembrane glycoproteins that mediate Ca²⁺-dependent homophilic cell-cell adhesion and play a crucial role in proliferation, differentiation, and cell transformation. The goal of this study was to understand why R-cadherin is found in rhabdomyosarcomas (RMS), tumors of skeletal muscle origin, whereas it is absent in normal myoblasts. We show that R-cadherin expression in C2C12 myoblasts causes inhibition of myogenesis induction and impairment of cell cycle exit when cells are cultured in differentiation medium. Furthermore, R-cadherin expression elicits myoblast transformation, as shown by anchorage-independent growth in soft agar in vivo tumor formation assays and increased cell motility. In contrast, inhibition of R-cadherin expression using RNA interference hinders growth of RD cell line in soft agar and its tumorigenicity in mice. The analysis of the nature of R-cadherin–mediated signals shows that R-cadherin–dependent adhesion increases Rac1 activity. Dominant-negative forms of Rac1 inhibit R-cadherin–mediated signaling and transformation. In addition, expression of R-cadherin results in perturbed function of endogenous N-cadherin and M-cadherin. Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. [Cancer Res 2008;68(16):6559–68]

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