title: Genetic inactivation of the pancreatitis-inducible gene Nupr1 impairs PanIN formation by modulating Kras(G12D)-induced senescence.
abstract: Nuclear protein 1 (Nupr1), a small chromatin protein, has a critical role in cancer development, progression and resistance to therapy. Previously, we had demonstrated that Nupr1 cooperates with Kras(G12D) to induce pancreas intraepithelial neoplasias (PanIN) formation and pancreatic ductal adenocarcinoma development in mice. However, the molecular mechanisms by which Nupr1 influences Kras-mediated preneoplastic growth remain to be fully characterized. In the current study, we report evidence supporting a role for Nupr1 as a gene modifier of Kras(G12D)-induced senescence, which must be overcome to promote PanIN formation. We found that genetic inactivation of Nupr1 in mice impairs Kras-induced PanIN, leading to an increase in β-galactosidase-positive cells and an upregulation of surrogate marker genes for senescence. More importantly, both of these cellular and molecular changes are recapitulated by the results of mechanistic experiments using RNAi-based inactivation of Nupr1 in human pancreatic cancer cell models. In addition, the senescent phenotype, which results from Nupr1 inactivation, is accompanied by activation of the FoxO3a-Skp2-p27(Kip1)-pRb-E2F pathway in vivo and in vitro. Thus, combined, these results show, for the first time, that Nupr1 aids oncogenic Kras to bypass senescence in a manner that cooperatively promotes PanIN formation. Besides its mechanistic importance, this new knowledge bears medical relevance as it delineates early pathobiological events that may be targeted in the future as a means to interfere with the formation of preneoplastic lesions early during pancreatic carcinogenesis.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Grasso
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: M N
authors.initials: MN
authors.lastname: Garcia
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: T
authors.initials: T
authors.lastname: Hamidi
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Cano
authors.affiliation: Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec City, QC, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Calvo
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: C436291:CDKN1B protein, human; D004268:DNA-Binding Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001616:beta-Galactosidase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)