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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Apoptosis
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Blotting, Western
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Cell Hypoxia*
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Cell Proliferation
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology*
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Cells, Cultured
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Fibroblasts / metabolism
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Fibroblasts / pathology*
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Glucose / metabolism
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Glycolysis*
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Homeodomain Proteins / physiology*
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Humans
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Immunoenzyme Techniques
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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Lactic Acid / metabolism
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Mice
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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Rats
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Survivin
Substances
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BIRC5 protein, human
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Homeodomain Proteins
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Inhibitor of Apoptosis Proteins
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MYCN protein, human
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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RNA, Messenger
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Survivin
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RAG-1 protein
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Lactic Acid
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Adenosine Triphosphate
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Glucose