Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity
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Lavinia Raimondi1, Nicola Amodio1, Maria Teresa Di Martino1, Emanuela Altomare1, Marzia Leotta1, Daniele Caracciolo1, Annamaria Gullà1, Antonino Neri2, Simona Taverna3, Patrizia D’Aquila4, Riccardo Alessandro3, Antonio Giordano5, Pierosandro Tagliaferri1 and Pierfrancesco Tassone1,5.
1 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy
2 Department of Medical Sciences University of Milan, Hematology1, IRCCS Policlinico Foundation, Milan, Italy
3 Department of Pathology and Forensic and Medical Biotechnology, Section of Biology and Genetics, University of Palermo, Italy
4 Department of Biology, Ecology and Earth Science (DiBEST),University of Calabria, Arcavacata di Rende, Cosenza, Italy
5 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Pierfrancesco Tassone, email:
Keywords: miR-199-5p, microRNA, miRNA, multiple myeloma, plasma cell leukemia, microenviroment, hypoxia, angiogenesis
Received: December 27, 2013 Accepted: March 12, 2014 Published: March 14, 2014
Multiple myeloma (MM) cells induce relevant angiogenic effects within the human bone marrow milieu (huBMM) by the aberrant expression of angiogenic factors. Hypoxia triggers angiogenic events within the huBMM and the transcription factor hypoxia-inducible factor-1α (HIF-1α) is over-expressed by MM cells. Since synthetic miR-199a-5p mimics negatively regulates HIF-1α, we here investigated a miRNA-based therapeutic strategy against hypoxic MM cells. We indeed found that enforced expression of miR-199a-5p led to down-modulated expression of HIF-1α as well as of other pro-angiogenic factors such as VEGF-A, IL-8, and FGFb in hypoxic MM cells in vitro. Moreover, miR-199a-5p negatively affected MM cells migration, while it increased the adhesion of MM cells to bone marrow stromal cells (BMSCs) in hypoxic conditions. Furthermore, transfection of MM cells with miR-199a-5p significantly impaired also endothelial cells migration and down-regulated the expression of endothelial adhesion molecules such as VCAM-1 and ICAM-1. Finally, we identified a hypoxia\AKT/miR-199a-5p loop as a potential molecular mechanism responsible of miR-199a-5p down-regulation in hypoxic MM cells. Taken together our results indicate that miR-199a-5p has an important role for the pathogenesis of MM and support the hypothesis that targeting angiogenesis via a miRNA/HIF-1α pathway may represent a novel potential therapeutical approach for this still lethal disease.
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