title: Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.
abstract: The introduction of new therapies against particular genetic mutations in non-small-cell lung cancer is a promising avenue for improving patient survival, but the target population is small. There is a need to discover new potential actionable genetic lesions, to which end, non-conventional cancer pathways, such as RNA editing, are worth exploring. Herein we show that the adenosine-to-inosine editing enzyme ADAR1 undergoes gene amplification in non-small cancer cell lines and primary tumors in association with higher levels of the corresponding mRNA and protein. From a growth and invasion standpoint, the depletion of ADAR1 expression in amplified cells reduces their tumorigenic potential in cell culture and mouse models, whereas its overexpression has the opposite effects. From a functional perspective, ADAR1 overexpression enhances the editing frequencies of target transcripts such as NEIL1 and miR-381. In the clinical setting, patients with early-stage lung cancer, but harboring ADAR1 gene amplification, have poor outcomes. Overall, our results indicate a role for ADAR1 as a lung cancer oncogene undergoing gene amplification-associated activation that affects downstream RNA editing patterns and patient prognosis.
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Anadón
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Guil
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Simó-Riudalbas
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Setien
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martínez-Cardús
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Moran
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, Barcelona, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Calaf
authors.affiliation: Department of Pathological Anatomy, Bellvitge Unviversity Hospital, Barcelona, Catalonia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Experimental Therapeutics and Translational Oncology Program, Instituto de Biologıa Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain.|Instituto de Investigacion Biomedica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: P A
authors.initials: PA
authors.lastname: Lazo
authors.affiliation: MRC-Holland, Amsterdam, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Zondervan
authors.affiliation: MRC-Holland, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Savola
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.|Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Catalonia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Institute for Research in Biomedicine (IRB), c/ Baldiri Reixac 10 08028, Barcelona, Catalonia, Spain.|Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Ribas de Pouplana
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain.|Institute for Research in Biomedicine (IRB), c/ Baldiri Reixac 10 08028, Barcelona, Catalonia, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Esteller
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D045744:Cell Line, Tumor; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D009857:Oncogenes; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D016601:RNA-Binding Proteins; C000595356:ADAR protein, human; D000243:Adenosine Deaminase; D016283:Proto-Oncogene Proteins p21(ras)