title: Stabilization of HIF-1α and HIF-2α, up-regulation of MYCC and accumulation of stabilized p53 constitute hallmarks of CNS-PNET animal model.
abstract: Recently, we described a new animal model of CNS primitive neuroectodermal tumors (CNS-PNET), which was generated by orthotopic transplantation of human Radial Glial (RG) cells into NOD-SCID mice's brain sub-ventricular zone. In the current study we conducted comprehensive RNA-Seq analyses to gain insights on the mechanisms underlying tumorigenesis in this mouse model of CNS-PNET. Here we show that the RNA-Seq profiles derived from these tumors cluster with those reported for patients' PNETs. Moreover, we found that (i) stabilization of HIF-1α and HIF-2α, which are involved in mediation of the hypoxic responses in the majority of cell types, (ii) up-regulation of MYCC, a key onco-protein whose dysregulation occurs in ~70% of human tumors, and (iii) accumulation of stabilized p53, which is commonly altered in human cancers, constitute hallmarks of our tumor model, and might represent the basis for CNS-PNET tumorigenesis in this model. We discuss the possibility that these three events might be interconnected. These results indicate that our model may prove invaluable to uncover the molecular events leading to MYCC and TP53 alterations, which would be of broader interest considering their relevance to many human malignancies. Lastly, this mouse model might prove useful for drug screening targeting MYCC and related members of its protein interaction network.
authors.affiliation: Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
authors.forename: Sergey
authors.initials: S
authors.lastname: Malchenko
authors.affiliation: Department of Surgery, Division of Pediatric Neurosurgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.|Cancer Biology and Epigenomics Program at the Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
authors.forename: Simone Treiger
authors.initials: ST
authors.lastname: Sredni
authors.affiliation: Department of Preventive Medicine, Division of Health and Biomedical Informatics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.|Abbvie Bioresearch Center, Worcester, Massachusetts, United States.
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, United States of America.
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.affiliation: Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
authors.forename: Jerusha
authors.initials: J
authors.lastname: Boyineni
authors.affiliation: Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
authors.forename: Indra
authors.initials: I
authors.lastname: Mohanam
authors.affiliation: Department of Surgery, Division of Pediatric Neurosurgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Department of Preventive Medicine, Division of Health and Biomedical Informatics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.affiliation: Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, United States of America.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse