Theranostics 2016; 6(8):1105-1118. doi:10.7150/thno.14700

Research Paper

MiR675-5p Acts on HIF-1α to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma

Alessia Lo Dico1,9*, Viviana Costa2*, Cristina Martelli3, Cecilia Diceglie3,4, Francesca Rajata5, Aroldo Rizzo5, Carmine Mancone6, Marco Tripodi6,7, Luisa Ottobrini3,8, Riccardo Alessandro9,10#✉, Alice Conigliaro6#✉

1. Tecnomed Foundation of the University of Milano-Bicocca, Monza 20900, Italy
2. Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo 90127, Italy
3. Department of Pathophysiology and Transplantation, University of Milan, Milan 20100, Italy;
4. Doctorate School of Molecular Medicine, University of Milan, Milan 20100, Italy;
5. Unità Operativa di Anatomia Patologica, Azienda Ospedaliera Ospedali Riuniti "Villa Sofia-Cervello", Palermo 90100, Italy;
6. Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome 00185, Italy;
7. National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome 00149, Italy;
8. Institute of Molecular Bioimaging and Physiology (IBFM), National Researches Council (CNR), Segrate (MI) 20093, Italy;
9. Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Palermo 90127, Italy;
10. Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council of Italy, Palermo 90146, Italy.
* these authors contributed equally to this work.
# joint senior authors.

Abstract

Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis.

Keywords: Angiogenesis, hypoxia, glioma, miRNA675, optical imaging, HuR, VHL.

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How to cite this article:
Lo Dico A, Costa V, Martelli C, Diceglie C, Rajata F, Rizzo A, Mancone C, Tripodi M, Ottobrini L, Alessandro R, Conigliaro A. MiR675-5p Acts on HIF-1α to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma. Theranostics 2016; 6(8):1105-1118. doi:10.7150/thno.14700. Available from http://www.thno.org/v06p1105.htm