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

Lavinia Raimondi, Nicola Amodio, Maria Teresa di Martino, Emanuela Altomare, Marzia Leotta, Daniele Caracciolo, Annamaria Gullà, Antonino Neri, Simona Taverna, Patrizia D'Aquila, Riccardo Alessandro, Antonio Giordano, Pierosandro Tagliaferri, Pierfrancesco Tassone

Research output: Contribution to journalArticle

62 Citations (Scopus)

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 languageEnglish
Pages (from-to)3039-3054
Number of pages16
JournalOncotarget
Volume5
Issue number10
Publication statusPublished - 2014

Fingerprint

Multiple Myeloma
Hypoxia-Inducible Factor 1
Neoplasms
Angiogenesis Inducing Agents
MicroRNAs
Cell Movement
Bone Marrow
In Vitro Techniques
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
Mesenchymal Stromal Cells
Interleukin-8
Vascular Endothelial Growth Factor A
Transfection
Transcription Factors
Down-Regulation
Endothelial Cells

Keywords

  • Angiogenesis
  • Hypoxia
  • Microenviroment
  • MicroRNA
  • miR-199-5p
  • MiRNA
  • Multiple myeloma
  • Plasma cell leukemia

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Raimondi, L., Amodio, N., di Martino, M. T., Altomare, E., Leotta, M., Caracciolo, D., ... Tassone, P. (2014). Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: In vitro and in vivo anti-tumor activity. Oncotarget, 5(10), 3039-3054.

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 journalArticle

Raimondi, L, Amodio, N, di Martino, MT, Altomare, E, Leotta, M, Caracciolo, D, Gullà, A, Neri, A, Taverna, S, D'Aquila, P, Alessandro, R, Giordano, A, Tagliaferri, P & Tassone, P 2014, 'Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: In vitro and in vivo anti-tumor activity', Oncotarget, vol. 5, no. 10, pp. 3039-3054.
Raimondi L, Amodio N, di Martino MT, Altomare E, Leotta M, Caracciolo D et al. Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: In vitro and in vivo anti-tumor activity. Oncotarget. 2014;5(10):3039-3054.
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. / Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics : In vitro and in vivo anti-tumor activity. In: Oncotarget. 2014 ; Vol. 5, No. 10. pp. 3039-3054.
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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

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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.

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