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Signaling and Regulation

An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

¹ Istituto per l'Endocrinologia e l'Oncologia Sperimentale del Consiglio Nazionale delle Ricerche "G. Salvatore"; ² Cell Biology and Preclinical Models Unit, Istituto Nazionale Tumori, Fondazione "G. Pascale," Naples, Italy; ³ CEA/DSV/DRM SHFJ, Institut National de la Sante et de la Recherche Medicale ERM 103, Orsay, France; and ⁴ Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France

Requests for reprints: Vittorio de Franciscis, Istituto per l'Endocrinologia e l'Oncologia Sperimentale del Consiglio Nazionale delle Ricerche "G. Salvatore," via Pansini 5, 80131 Naples, Italy. Phone: 39-817462036; Fax: 39-817703285. E-mail: defranci{at}unina.it

In several neuroblastoma cell lines, retinoic acid (RA)–induced differentiation is coupled to increased expression of functional neurotrophic factor receptors, including Trk family receptors and the glial cell–derived neurotrophic factor receptor, Ret. In several cases, increased expression is dependent on signaling through TrkB. Unlike TrkA and TrkB, Ret has never been implicated as a prognostic marker for neuroblastomas. SK-N-BE(2) cells do not express any of Trk family receptors; therefore, they are a choice system to study the specific role of Ret in RA-induced differentiation. Using a 2'-fluoro-RNA aptamer and a truncated Ret protein as specific inhibitors of Ret, we show that RA-induced differentiation is mediated by a positive autocrine loop that sustains Ret downstream signaling and depends on glial cell–derived neurotrophic factor expression and release. This report shows that in SK-N-BE(2) cells, stimulation of Ret is a major upstream mechanism needed to mediate RA-induced differentiation. These results provide important insights on the molecular mechanism of RA action, which might be relevant for the development of biologically based therapeutic strategies. (Mol Cancer Res 2006;4(7):481–8)

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