title: MYCN and survivin cooperatively contribute to malignant transformation of fibroblasts.
abstract: The oncogenes MYCN and survivin (BIRC5) maintain aggressiveness of diverse cancers including sarcomas. To investigate whether these oncogenes cooperate in initial malignant transformation, we transduced them into Rat-1 fibroblasts. Indeed, survivin enhanced MYCN-driven contact-uninhibited and anchorage-independent growth in vitro. Importantly, upon subcutaneous transplantation into mice, cells overexpressing both instead of either one of the oncogenes generated tumors with shortened latency, marked anaplasia and an increased proliferation-to-apoptosis ratio resulting in accelerated growth. Mechanistically, the increased tumorigenicity was associated with an enhanced Warburg effect and a hypoxia inducible factor 1α linked vascular remodeling. This cooperation between MYCN and survivin may be important in the genesis of several cancers.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm89075, Germany.
authors.forename: Nora I
authors.initials: NI
authors.lastname: Hipp
authors.forename: Lisa
authors.initials: L
authors.lastname: Christner
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: Stefan
authors.initials: S
authors.lastname: Walenta
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Christian
authors.initials: C
authors.lastname: Beltinger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D000077022:Survivin; C064658:RAG-1 protein; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D005947:Glucose