title: Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells.
abstract: Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogen-associated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Antoine
authors.initials: A
authors.lastname: Tanne
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Muniz
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903;
authors.forename: Anna
authors.initials: A
authors.lastname: Puzio-Kuter
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Katerina I
authors.initials: KI
authors.lastname: Leonova
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.affiliation: Massachusetts General Hospital, Charlestown, MA 02129;
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Laboratoire de Physique Théorique, CNRS and Ecole Normale Supérieure, 75005 Paris, France;
authors.forename: Rémi
authors.initials: R
authors.lastname: Monasson
authors.affiliation: Laboratoire de Physique Statistique, CNRS and Ecole Normale Supérieure, 75005 Paris, France;
authors.forename: Simona
authors.initials: S
authors.lastname: Cocco
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903; The Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, NJ 08540; alevine@ias.edu benjamin.greenbaum@mssm.edu.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology, and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; The Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, NJ 08540; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 alevine@ias.edu benjamin.greenbaum@mssm.edu.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Greenbaum
mesh_terms: D000818:Animals; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D022661:RNA, Untranslated / Q000276:immunology*
chemical_list: D022661:RNA, Untranslated
keywords: cancer immunology; genome evolution; noncoding RNA