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.
| Original language | English |
|---|---|
| Pages (from-to) | 3039-3054 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 5 |
| Issue number | 10 |
| Publication status | Published - 2014 |
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Keywords
- Angiogenesis
- Hypoxia
- Microenviroment
- MicroRNA
- miR-199-5p
- MiRNA
- Multiple myeloma
- Plasma cell leukemia
ASJC Scopus subject areas
- Oncology
- Medicine(all)
Cite this
Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics : In vitro and in vivo anti-tumor activity. / 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.
In: Oncotarget, Vol. 5, No. 10, 2014, p. 3039-3054.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics
T2 - In vitro and in vivo anti-tumor activity
AU - Raimondi, Lavinia
AU - Amodio, Nicola
AU - di Martino, Maria Teresa
AU - Altomare, Emanuela
AU - Leotta, Marzia
AU - Caracciolo, Daniele
AU - Gullà, Annamaria
AU - Neri, Antonino
AU - Taverna, Simona
AU - D'Aquila, Patrizia
AU - Alessandro, Riccardo
AU - Giordano, Antonio
AU - Tagliaferri, Pierosandro
AU - Tassone, Pierfrancesco
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Hypoxia
KW - Microenviroment
KW - MicroRNA
KW - miR-199-5p
KW - MiRNA
KW - Multiple myeloma
KW - Plasma cell leukemia
UR - http://www.scopus.com/inward/record.url?scp=84902085012&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902085012&partnerID=8YFLogxK
M3 - Article
C2 - 24839982
AN - SCOPUS:84902085012
VL - 5
SP - 3039
EP - 3054
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 10
ER -