title: A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.
abstract: TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Justin
authors.initials: J
authors.lastname: Middleton
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Taewan
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laganà
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; Department of Experimental Oncology and Molecular Medicine, Start Up Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy;
authors.forename: Claudia
authors.initials: C
authors.lastname: Piovan
authors.affiliation: Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, 44100 Ferrara, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Ri
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Pooja
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.affiliation: Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712;
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea;
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Paolo
authors.initials: P
authors.lastname: Fadda
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.affiliation: Transcriptional Networks in Lung Cancer Group, Cancer Research United Kingdom Manchester Institute, University of Manchester, Manchester M20 4BX, United Kingdom michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210; michela.garofalo@cruk.manchester.ac.uk carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand
keywords: acquired TRAIL-resistance; lung cancer; microRNAs