title: Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers.
abstract: Purpose:The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.Experimental Design:We performedin vitrostudies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used anin vivoorthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 andTP53expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.Results:We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agentsin vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapyin vivoWe show that anti-miR-155-DOPC can be considered non-toxicin vivoWe further demonstrate that miR-155 andTP53are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression ofTP53is significantly associated with shorter survival in lung cancer.Conclusions:Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.Clin Cancer Res; 23(11); 2891-904. ©2016 AACR.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Roosbroeck
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fanini
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Setoyama
authors.affiliation: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Fuentes-Mattei
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lianchun
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Vannini
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Roxana S
authors.initials: RS
authors.lastname: Redis
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: D'Abundo
authors.affiliation: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Milena S
authors.initials: MS
authors.lastname: Nicoloso
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Departamento de Biologia Celular y Genetica, Universidad Autonoma de Nuevo Leon, 66450 San Nicolas de los Garza, Nuevo Leon, Mexico.
authors.forename: Vianey
authors.initials: V
authors.lastname: Gonzalez-Villasana
authors.affiliation: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna 40126, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.affiliation: Department of Onco-Hematology, A.O. of Cosenza, Cosenza 87100, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milano and Hematology, Ospedale Policlinico, Milano 20122, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Vivian R
authors.initials: VR
authors.lastname: Ruvolo
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Unit of Gene Therapy, Meldola (FC) 47014, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Abruzzo
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steliana
authors.initials: S
authors.lastname: Calin
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Orlowski
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Lichtenberg
authors.affiliation: Department of Preventive Medicine - Division of Health and Biomedical Informatics, Northwestern University - Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.affiliation: Department of Functional Genomics, The Oncology Institute, 400015 Cluj-Napoca, Romania.|Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy Iuliu Hatieganu, 400012 Cluj-Napoca, Romania.
authors.forename: Ioana
authors.initials: I
authors.lastname: Berindan-Neagoe
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Departments of Pediatrics and Molecular Microbiology & Immunology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Saban.
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000070416:Antagomirs; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin