Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma.

J Natl Cancer Inst

Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue,' LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France (BG, CDB, OM, SLG, JF, BD, FL, MC, AMN, PM); CNRS UMR 8126, University Paris-Sud 11, Institut Gustave Roussy, Villejuif, France (C-HG, JB); Stem Cell and Brain Research Institute, INSERM U846, Bron, France (FB); INSERM, U830, Génétique et Biologie des Cancers, Institut Curie, Paris, France (IJL, OD); Department Epigenetics and Cancer FRE 3377, Centre National de la Recherche Scientifique, Commissariat à l'Energie Atomique Saclay, Gif-sur-Yvette, France (AHB); Université Paris-Sud, Gif-sur-Yvette, France (AH-B); Present address: INSERM UMR 1078, Etablissement Français du Sang, Centre Hospitalier Régional Universitaire de Brest, SFR ScInBioS, Université de Bretagne Occidentale, Faculté de Médecine, Brest, France (C-HG).

Published: November 2014

Background: The Sonic Hedgehog (SHH) signaling pathway plays an important role in neural crest cell fate during embryonic development and has been implicated in the progression of multiple cancers that include neuroblastoma, a neural crest cell-derived disease. While most of the SHH signaling is mediated by the well-described canonical pathway leading to the activation of Smoothened and Gli, it has recently been shown that cell-adhesion molecule-related/downregulated by oncogenes (CDON) serves as a receptor for SHH and contributes to SHH-induced signaling. CDON has also been recently described as a dependence receptor, triggering apoptosis in the absence of SHH. This CDON proapoptotic activity has been suggested to constrain tumor progression.

Methods: CDON expression was analyzed by quantitative-reverse transcription-polymerase chain reaction in a panel of 226 neuroblastoma patients and associated with stages, overall survival, and expression of miR181 family members using Kaplan Meier and Pearson correlation methods. Cell death assays were performed in neuroblastoma cell lines and tumor growth was investigated in the chick chorioallantoic model. All statistical tests were two-sided.

Results: CDON expression was inversely associated with neuroblastoma aggressiveness (P < .001). Moreover, re-expression of CDON in neuroblastoma cell lines was associated with apoptosis in vitro and tumor growth inhibition in vivo. We show that CDON expression is regulated by the miR181 miRNA family, whose expression is directly associated with neuroblastoma aggressiveness (survival: high miR181-b 73.2% vs low miR181-b 54.6%; P = .03).

Conclusions: Together, these data support the view that CDON acts as a tumor suppressor in neuroblastomas, and that CDON is tightly regulated by miRNAs.

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http://dx.doi.org/10.1093/jnci/dju318DOI Listing

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