title: MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness.
abstract: Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.
authors.affiliation: Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Planells-Ferrer
authors.affiliation: Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Urresti
authors.affiliation: Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Reix
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: D M
authors.initials: DM
authors.lastname: Murphy
authors.affiliation: Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Ferreres
authors.affiliation: Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Borràs
authors.affiliation: 1] Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Gallego
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: R L
authors.initials: RL
authors.lastname: Stallings
authors.affiliation: Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: R S
authors.initials: RS
authors.lastname: Moubarak
authors.affiliation: Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Segura
authors.affiliation: Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J X
authors.initials: JX
authors.lastname: Comella
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004318:Doxycycline / Q000633:toxicity; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; C400427:FAIM2 protein, human; C459801:MYCN protein, human; D008565:Membrane Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D014212:Tretinoin; D004318:Doxycycline