title: cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas.
abstract: Successful/effective cancer therapy in low grade lymphoma is often hampered by cell resistance to anti-neoplastic agents. The crucial mechanisms responsible for this phenomenon are poorly understood. Overcoming resistance of tumor cells to anticancer agents, such as proteasome inhibitors, could improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where xenotransplantation of human CTCL cells overexpressing miR-125b-5p resulted in enhanced tumor growth and a shorter median survival. Our findings describe a novel mechanism through which miR-125b-5p not only regulates tumor growth in vivo, but also increases cellular resistance to proteasome inhibitors via modulation of MAD4.
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark. valentinamanfe@libero.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Manfè
authors.forename: Edyta
authors.initials: E
authors.lastname: Biskup
authors.forename: Ayalah
authors.initials: A
authors.lastname: Willumsgaard
authors.forename: Anne Guldhammer
authors.initials: AG
authors.lastname: Skov
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laganá
authors.forename: Anders
authors.initials: A
authors.lastname: Woetmann
authors.forename: Niels
authors.initials: N
authors.lastname: Ødum
authors.forename: Carlo Maria
authors.initials: CM
authors.lastname: Croce
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008156:Luciferases; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001897:Boronic Acids; D000069286:Bortezomib; D017931:DNA Primers; D008156:Luciferases; D035683:MicroRNAs; D061988:Proteasome Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C484347:MXD4 protein, human; C489427:MYC protein, human; C527468:Mirn125 microRNA, mouse