title: Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma.
abstract: 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.
authors.affiliation: 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).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gibert
authors.affiliation: 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).
authors.forename: Céline
authors.initials: C
authors.lastname: Delloye-Bourgeois
authors.affiliation: 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).
authors.forename: Charles-Henry
authors.initials: CH
authors.lastname: Gattolliat
authors.affiliation: 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).
authors.forename: Olivier
authors.initials: O
authors.lastname: Meurette
authors.affiliation: 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).
authors.forename: Solen
authors.initials: S
authors.lastname: Le Guernevel
authors.affiliation: 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).
authors.forename: Joanna
authors.initials: J
authors.lastname: Fombonne
authors.affiliation: 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).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ducarouge
authors.affiliation: 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).
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lavial
authors.affiliation: 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).
authors.forename: Frantz
authors.initials: F
authors.lastname: Bouhallier
authors.affiliation: 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).
authors.forename: Marion
authors.initials: M
authors.lastname: Creveaux
authors.affiliation: 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).
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Negulescu
authors.affiliation: 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).
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.affiliation: 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).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.affiliation: 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).
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.affiliation: 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).
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: 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). patrick.mehlen@lyon.unicancer.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C107286:CDON protein, human; D015815:Cell Adhesion Molecules; D053823:Hedgehog Proteins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins