Manfè, Valentina2; Biskup, Edyta3; Willumsgaard, Ayalah3; Skov, Anne Guldhammer3; Palmieri, Dario3; Gasparini, Pierluigi3; Laganá, Alessandro3; Andersen, Anders Woetmann4; Ødum, Niels4; Croce, Carlo Maria3; Gniadecki, Robert3
1 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark. email@example.com unknown4 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Plos One, 2013, Vol 8, Issue 3
Animals; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Boronic Acids; Chromatin Immunoprecipitation; Computational Biology; DNA Primers; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; In Situ Hybridization; Kaplan-Meier Estimate; Luciferases; Lymphoma, T-Cell; Mice; MicroRNAs; Proteasome Inhibitors; Proto-Oncogene Proteins c-myc; Pyrazines; RNA, Small Interfering; Repressor Proteins; Signal Transduction; Skin Neoplasms