Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity.

Content Provider	Europe PMC
Author	Raimondi, Lavinia Amodio, Nicola Di Martino, Maria Teresa Altomare, Emanuela Leotta, Marzia Caracciolo, Daniele Gullà, Annamaria Neri, Antonino Taverna, Simona D'Aquila, Patrizia Alessandro, Riccardo Giordano, Antonio Tagliaferri, Pierosandro Tassone, Pierfrancesco
Copyright Year	2014
Abstract	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.
Journal	Oncotarget
Volume Number	5
PubMed Central reference number	PMC4102790
Issue Number	10
PubMed reference number	24839982
e-ISSN	19492553
DOI	10.18632/oncotarget.1747
Language	English
Publisher	Impact Journals LLC
Publisher Date	2014-05-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2014 Raimondi et al.
Subject Keyword	miR-199-5p microRNA miRNA multiple myeloma plasma cell leukemia microenviroment hypoxia angiogenesis
Content Type	Text
Resource Type	Article
Subject	Oncology